Imidazole derivatives with biphenylsulfonyl substitution method for preparing them and their use as a drug or diagnostic agent

ABSTRACT

The invention relates to compounds of formula (I), wherein the symbols have the meanings indicated in the specification. The inventive compounds exhibit dramatic antiarrhythmic proprieties and contain a cardioprotective compound. They can preventively inhibit or strongly reduce pathophysiologic processes upon occurrence of ischemic injuries, especially ischemic cardiac arrhythmia. Said compounds also exhibit a strong inhibiting effect on cellular proliferation.

This application is a national stage filing under 35 U.S.C. §371 ofinternational application no. PCT/EP99/04887, filed Jul. 10, 1999.

The invention relates to compounds of the formula I

in which the symbols have the following meaning:

R(1) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or—C_(a)H_(2a)-phenyl, where the phenyl moiety is unsubstituted orsubstituted by 1, 2 or 3 identical or different radicals from the groupconsisting of F, Cl, Br, I, CF₃, methyl, methoxy, hydroxyl or NR(8)R(9);

R(8) and R(9) independently of one another are hydrogen or alkyl having1, 2, 3 or 4 carbon atoms;

a is zero, 1 or 2; or

R(1) is —C_(b)H_(2b)-heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9carbon atoms, where the heteroaryl moiety is unsubstituted orsubstituted by 1, 2 or 3 identical or different radicals from the groupconsisting of F, Cl, Br, I, CF₃, methyl, methoxy, hydroxyl orNR(10)R(11);

R(10) and R(11) independently of one another are hydrogen or alkylhaving 1, 2, 3 or 4 carbon atoms;

b is zero, 1 or 2; or

R(1) is —C_(d)H_(2d)-cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;

d is zero, 1 or 2;

R(2) and R(3) independently of one another are hydrogen, F, Cl, Br, I,CF₃, —CN, —NO₂, CH₂OR(17), CO—R(6), O—R(7), O-(alkylene having 2, 3 or 4carbon atoms)-O—R(17) or NR(50)R(51);

R(17) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;

R(6) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,OR(30) or phenyl which is unsubstituted or substituted by 1, 2 or 3identical or different radicals from the group consisting of F, Cl, Br,I, CF₃, methyl, methoxy, hydroxyl or NR(31)R(32);

R(31) and R(32) independently of one another are hydrogen or alkylhaving 1, 2, 3 or 4 carbon atoms;

R(30) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;

R(50) and R(51) independently of one another are -(alkylene having 2, 3or 4 carbon atoms)-O—R(52); R(52) is hydrogen or alkyl having 1, 2, 3,4, 5, 6, 7 or 8 carbon atoms;

R(7) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, orphenyl, which is unsubstituted or substituted by 1, 2 or 3 identical ordifferent radicals from the group consisting of F, Cl, Br, I, CF₃,methyl, methoxy, hydroxyl or NR(12)R(13);

R(12) and R(13) independently of one another are hydrogen or alkylhaving 1, 2, 3 or 4 carbon atoms; or

R(7) is heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,which is unsubstituted or substituted by 1, 2 or 3 identical ordifferent radicals from the group consisting of F, Cl, Br, I, CF₃,methyl, methoxy, hydroxyl or NR(14)R(15);

R(14) and R(15) independently of one another are hydrogen or alkylhaving 1, 2, 3 or 4 carbon atoms; or

R(2) and R(3) independently of one another are alkyl having 1, 2, 3, 4,5, 6, 7 or 8 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbonatoms or —C_(g)H_(2g)-phenyl, where the phenyl moiety is unsubstitutedor substituted by 1, 2 or 3 identical or different radicals from thegroup consisting of F, Cl, Br, I, CF₃, methyl, methoxy, hydroxyl orNR(18)R(19);

R(18) and R(19) independently of one another are hydrogen or alkylhaving 1, 2, 3 or 4 carbon atoms;

g is zero, 1 or 2; or

R(2) and R(3) independently of one another are —C_(l)H_(2l)-heteroarylhaving 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, where the heteroarylmoiety is unsubstituted or substituted by 1, 2 or 3 identical ordifferent radicals from the group consisting of F, Cl, Br, I, CF₃,methyl, methoxy, hydroxyl or NR(20)R(21);

R(20) and R(21) independently of one another are hydrogen or alkylhaving 1, 2, 3 or 4 carbon atoms;

l is zero, 1 or 2; or

R(2) and R(3) independently of one another are SO_(n)—R(22);

n is zero, 1 or 2;

R(22) is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkylhaving 3, 4, 5, 6 or 7 carbon atoms or —C_(S)C_(2s)-phenyl which isunsubstituted or substituted by 1, 2 or 3 identical or differentradicals from the group consisting of F, Cl, Br, I, CF₃, methyl,methoxy, hydroxyl or NR(34)R(35);

R(34) and R(35) independently of one another are hydrogen or alkylhaving 1, 2, 3 or 4 carbon atoms;

s is zero, 1 or 2;

R(4) and R(5) independently of one another are hydrogen, alkyl having 1,2, 3, 4, 5, 6, 7 or 8 carbon atoms, F, Cl, Br, I, CF₃, —CN, —NO₂,SO_(p)—R(16), CO—R(23), O—R(24) or O-(alkylene having 2, 3 or 4 carbonatoms)-O—R(33);

p is zero, 1 or 2;

R(16) is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl,which is unsubstituted or substituted by 1, 2 or 3 identical ordifferent radicals from the group consisting of F, Cl, Br, I, CF₃,methyl, methoxy, hydroxyl or NR(26)R(27);

R(26) and R(27) independently of one another are hydrogen or alkylhaving 1, 2, 3 or 4 carbon atoms;

R(23) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms orOR(25);

R(25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;

R(24) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms orphenyl, which is unsubstituted or substituted by 1, 2 or 3 identical ordifferent radicals from the group consisting of F, Cl, Br, I, CF₃,methyl, methoxy, hydroxyl or NR(28)R(29);

R(28) and R(29) independently of one another are hydrogen or alkylhaving 1, 2, 3 or 4 carbon atoms;

R(33) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;

or their physiologically tolerable salts;

with the proviso that at least one of the radicals R(2) or R(3) isO-(alkylene having 2, 3 or 4 carbon atoms)-O—R(17) or NR(50)R(51).

Preferred compounds of the formula I are those in which:

R(1) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or—C_(a)H_(2a)-phenyl, where the phenyl moiety is unsubstituted orsubstituted by 1 or 2 identical or different radicals from the groupconsisting of F, Cl, Br, CF₃, methyl, methoxy, hydroxyl or NR(8)R(9);

R(8) and R(9) independently of one another are hydrogen or methyl;

a is zero or 1; or

R(1) is heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms whichis unsubstituted or substituted by a radical from the group consistingof F, Cl, Br, CF₃, CH₃, methoxy, hydroxyl or NR(10)R(11);

R(10) and R(11) independently of one another are hydrogen or methyl; or

R(1) is —C_(d)H_(2d)-cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;

d is zero or 1;

R(2) and R(3) independently of one another are hydrogen, F, Cl, Br, CF₃,—CN, —NO₂, CH₂OR(17), CO—R(6), O—R(7), O-(alkylene having 2 or 3 carbonatoms)-O—R(17) or NR(50)R(51);

R(17) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

R(6) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, OR(30) orphenyl, which is unsubstituted or substituted by 1 or 2 identical ordifferent radicals from the group consisting of F, Cl, Br, CF₃, methyl,methoxy, hydroxyl or NR(31)R(32);

R(31) and R(32) independently of one another are hydrogen or methyl;

R(30) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

R(7) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,which is unsubstituted or substituted by 1 or 2 identical or differentradicals from the group consisting of F, Cl, Br, CF₃, methyl, methoxy,hydroxyl or NR(12)R(13);

R(12) and R(13) independently of one another are hydrogen or methyl; or

R(7) is heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,which is unsubstituted or substituted by 1 or 2 identical or differentradicals from the group consisting of F, Cl, Br, CF₃, methyl, methoxy,hydroxyl or NR(14)R(15);

R(14) and R(15) independently of one another are hydrogen or methyl;

R(50) and R(51) independently of one another are -(alkylene having 2 or3 carbon atoms)-O—R(52);

R(52) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; or

R(2) and R(3) independently of one another are alkyl having 1, 2, 3 or 4carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or—C_(g)H_(2g)-phenyl, where the phenyl moiety is unsubstituted orsubstituted by 1 or 2 identical or different radicals from the groupconsisting of F, Cl, Br, CF₃, methyl, methoxy, hydroxyl or NR(18)R(19);

R(18) and R(19) independently of one another are hydrogen or methyl;

g is zero or 1; or

R(2) and R(3) independently of one another are heteroaryl having 1, 2,3, 4, 5, 6, 7, 8 or 9 carbon atoms, which is unsubstituted orsubstituted by a radical from the group consisting of F, Cl, Br, CF₃,methyl, methoxy, hydroxyl or NR(20)R(21);

R(20) and R(21) independently of one another are hydrogen or methyl; or

R(2) and R(3) independently of one another are SO_(n)—R(22),

n is zero, 1 or 2;

R(22) is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4,5, 6 or 7 carbon atoms or —C_(s)H_(2s)-phenyl, where the phenyl moietyis unsubstituted or substituted by 1 or 2 identical or differentradicals from the group consisting of F, Cl, Br, CF₃, methyl, methoxy,hydroxyl or NR(34)R(35);

R(34) and R(35) independently of one another are hydrogen or methyl;

s is zero or 1;

R(4) and R(5) independently of one another are hydrogen, alkyl having 1,2, 3 or 4 carbon atoms, F, Cl, Br, CF₃, —CN, —NO₂, SO_(p)—R(16),CO—R(23), O—R(24) or O-(alkylene having 2 or 3 carbon atoms)-O—R(33);

p is zero, 1 or 2;

R(16) is alkyl having 1, 2, 3 or 4 carbon atoms or phenyl, which isunsubstituted or substituted by 1 or 2 identical or different radicalsfrom the group consisting of F, Cl, Br, CF₃, methyl, methoxy, hydroxylor NR(26)R(27);

R(26) and R(27) independently of one another are hydrogen or methyl;

R(23) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or OR(25);

R(25) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

R(24) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,which is unsubstituted or substituted by 1 or 2 identical or differentradicals from the group consisting of F, Cl, Br, CF₃, methyl, methoxy,hydroxyl or NR(28)R(29);

R(28) and R(29) independently of one another are hydrogen or methyl;

R(33) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

or their physiologically tolerable salts;

with the proviso that at least one of the radicals R(2) or R(3) isO-(alkylene having 2 or 3 carbon atoms)-O—R(17) or NR(50)R(51).

Particularly preferred compounds of the formula I are those in which:

R(1) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,which is unsubstituted or substituted by a radical from the groupconsisting of F, Cl, Br, CF₃, methyl, methoxy, hydroxyl or NR(8)R(9);

R(8) and R(9) independently of one another are hydrogen or methyl; or

R(1) is heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,which is unsubstituted or substituted by a radical from the groupconsisting of F, Cl, Br, CF₃, methyl, methoxy, hydroxyl or NR(10)R(11);

R(10) and R(11) independently of one another are hydrogen or methyl; or

R(1) is cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;

R(2) and R(3) independently of one another are hydrogen, F, Cl, Br, CF₃,—CN, —NO₂, CO—R(6), O—R(7), O—CH₂—CH₂—O—R(17) or NR(50)R(51);

R(6) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, OR(30) orphenyl, which is unsubstituted or substituted by a radical from thegroup consisting of F, Cl, Br, CF₃, methyl, methoxy, hydroxyl orNR(31)R(32);

R(31) and R(32) independently of one another are hydrogen or methyl;

R(30) is hydrogen or alkyl having 1, 2 or 3 carbon atoms:

R(7) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,which is unsubstituted or substituted by a radical from the groupconsisting of F, Cl, Br, methyl, methyl, methoxy, hydroxyl orNR(12)R(13);

R(12) and R(13) independently of one another are hydrogen or methyl; or

R(7) is heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,which is unsubstituted or substituted by a radical from the groupconsisting of F, Cl, Br, CF₃, methyl, methoxy, hydroxyl or NR(14)R(15);

R(14) and R(15) independently of one another are hydrogen or methyl;

R(17) is methyl or ethyl;

R(50) and R(51) independently of one another are —CH₂—CH₂—O—R(52); R(52)is methyl or ethyl; or

R(2) and R(3) independently of one another are alkyl having 1, 2, 3 or 4carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or phenyl,which is unsubstituted or substituted by a radical from the groupconsisting of F, Cl, Br, CF₃, methyl, methoxy, hydroxyl or NR(18)R(19);

R(18) and R(19) independently of one another are hydrogen or methyl; or

R(2) and R(3) independently of one another are heteroaryl having 1, 2,3, 4, 5, 6, 7, 8 or 9 carbon atoms, which is unsubstituted orsubstituted by a radical from the group consisting of F, Cl, Br, CF₃,CH₃, methoxy, hydroxyl or

NR(20)R(21);

R(20) and R(21) independently of one another are hydrogen or methyl; or

R(2) and R(3) independently of one another are SO_(n)—R(22);

n is zero or 2;

R(22) is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4,5, 6 or 7 carbon atoms or phenyl which is unsubstituted or substitutedby 1 or 2 identical or different radicals from the group consisting ofF, Cl, Br, CF₃, methyl, methoxy, hydroxyl or NR(34)R(35);

R(34) and R(35) independently of one another are hydrogen or methyl;

R(4) and R(5) independently of one another are hydrogen, alkyl having 1,2, 3 or 4 carbon atoms, F, Cl, CF₃, —CN, —NO₂, SO_(p)—R(16), CO—R(23),O—R(24) or O—CH₂—CH₂—O—R(33);

p is zero or 2;

R(23) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or OR(25);

R(25) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

R(24) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,which is unsubstituted or substituted by a radical from the groupconsisting of F, Cl, Br, CF₃, methyl, methoxy, hydroxyl or NR(28)R(29);

R(28) and R(29) independently of one another are hydrogen or methyl;

R(16) is alkyl having 1, 2, 3 or 4 carbon atoms or phenyl which isunsubstituted or substituted by a radical from the group consisting ofF, Cl, Br, CF₃, methyl, methoxy, hydroxyl or NR(26)R(27);

R(26) and R(27) independently of one another are hydrogen or methyl;

R(33) is methyl or ethyl; or their physiologically tolerable salts;

with the proviso that at least one of the radicals R(2) or R(3) isO—CH₂—CH₂—O—R(17) or NR(50)R(51).

Very particularly preferred compounds of the formula I are those inwhich:

R(1) is alkyl having 1, 2, 3 or 4 carbon atoms or phenyl which isunsubstituted or substituted by a radical from the group consisting ofF, Cl, CF₃, methyl or methoxy; or

R(1) is heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,which is unsubstituted or substituted by a radical from the groupconsisting of F, Cl, CF₃, methyl or methoxy; or

R(1) is cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;

R(2) and R(3) independently of one another are hydrogen, F, Cl, CF₃,—CN, CO—R(6), O—R(7), O—CH₂—CH₂—O—CH₃CH₃or NR(50)R(51);

R(6) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, OR(30) orphenyl, which is unsubstituted or substituted by a radical from thegroup consisting of F, Cl, CF₃, methyl or methoxy;

R(30) is hydrogen, methyl or ethyl;

R(7) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,which is unsubstituted or substituted by a radical from the groupconsisting of F, Cl, CF₃, methyl or methoxy; or

R(7) is heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,which is unsubstituted or substituted by a radical from the groupconsisting of F, Cl, Br, CF₃, methyl or methoxy;

R(50) and R(51) are —CH₂—CH₂—O—CH₃; or

R(2) and R(3) independently of one another are alkyl having 1, 2, 3 or 4carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or phenyl,which is unsubstituted or substituted by a radical from the groupconsisting of F, Cl, CF₃, methyl and methoxy; or

R(2) and R(3) independently of one another are heteroaryl having 1, 2,3, 4, 5, 6, 7, 8 or 9 carbon atoms, which is unsubstituted orsubstituted by a radical from the group consisting of F, Cl, CF₃, methylor methoxy; or

R(2) and R(3) independently of one another are SO_(n)—R(22);

n is zero or 2;

R(22) is alkyl having 1, 2, 3 or 4 carbon atoms or phenyl which isunsubstituted or substituted by 1 or 2 identical or different radicalsfrom the group consisting of F, Cl, CF₃, methyl or methoxy;

R(4) and R(5) independently of one another are hydrogen, methyl, F, Cl,CF₃, —CN, SO₂—R(16), CO—R(23), O—R(24) or O—CH₂—CH₂—O—CH₃;

R(16) is alkyl having 1, 2, 3 or 4 carbon atoms or phenyl which isunsubstituted or substituted by a radical from the group consisting ofF, Cl, CF₃, methyl or methoxy;

R(23) is hydrogen, methyl or OR(25); R(25) is hydrogen, methyl or ethyl;

R(24) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,which is unsubstituted or substituted by a radical from the groupconsisting of F, Cl, CF₃, methyl or methoxy;

or their physiologically tolerable salts;

In addition, preferred compounds are those in which:

R(1) is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,—C_(d)H_(2d-)cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms where d isequal to zero, 1 or 2 or —C_(a)H_(2a)-phenyl, where the phenyl moiety isunsubstituted or substituted by 1, 2 or 3 identical or differentradicals from the group consisting of F, Cl, Br, I, CF₃, methyl,methoxy, hydroxyl or NR(8)R(9);

R(8) and R(9) independently of one another are hydrogen or alkyl having1, 2, 3 or 4 carbon atoms;

a is zero, 1 or 2;

R(2) is O-(alkylene having 2, 3 or 4 carbon atoms)-O—R(17) orNR(50)R(51);

R(17) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;

R(50) and R(51) independently of one another are -(alkylene having 2, 3or 4 carbon atoms)-O—R(52);

R(52) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;

R(3) is hydrogen, —CN or CO—R(6);

R(6) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms orOR(30);

R(30) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;

R(4) is hydrogen, Cl, F, Br, I, SO_(p)—R(16) or O—CH₂—CH₂—O—R(33);

p is zero, 1 or 2;

R(16) is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenylwhich is unsubstituted or substituted by 1, 2 or 3 identical ordifferent radicals from the group consisting of F, Cl, Br, I, CF₃,methyl, methoxy, hydroxyl or NR(26)R(27);

R(26) and R(27) independently of one another are hydrogen or alkylhaving 1, 2, 3 or 4 carbon atoms;

R(33) is methyl or ethyl;

(5) is hydrogen;

or their physiologically tolerable salts.

Preferred compounds are also those in which:

R(1) is —C_(a)H_(2a)-phenyl, where the phenyl moiety is unsubstituted orsubstituted by 1 or 2 identical or different radicals from the groupconsisting of F, Cl, Br, CF₃, methyl, methoxy, hydroxyl or NR(8)R(9);

R(8) and R(9) independently of one another are hydrogen or methyl;

a is zero or 1;

R(2) is O—(alkylene having 2, 3 or 4 carbon atoms)—O—R(17) orNR(50)R(51);

R(17) is alkyl having 1, 2, 3 or 4 carbon atoms, in particular methyl;

R(50) and R(51) independently of one another are -(alkylene having 2, 3or 4 carbon atoms)-O—R(52);

R(52) is alkyl having 1, 2, 3 or 4 carbon atoms, in particular methyl;

R(3) is CO—R(6);

R(6) is hydrogen;

R(4) is SO₂R(16) where R(16) is alkyl having 1, 2, 3 or 4 carbon atoms,in particular methyl or O—CH₂—CH₂—O—CH₃;

R(5) is hydrogen;

and their physiologically tolerable salts.

Particularly preferred compounds of the formula I are those in whichR(2) is O—CH₂—CH₂—O—R(17) or NR(50)R(51) where R(17) is equal to alkylhaving 1, 2, 3 or 4 carbon atoms, in particular methyl and R(50) andR(51) is equal to —CH₂—CH₂—O—R(52) where R(52) is equal to alkyl having1, 2, 3 or 4 carbon atoms, in particular methyl; and R(1), R(3), R(4)and R(5) are as defined above, and their physiologically tolerablesalts.

In addition, preferred compounds of the formula I are also those inwhich radicals R(1), R(2), R(3), R(4) and R(5) are as defined above andthe biphenyl substituent is linked as in formula Ia, Ib, Ic, Id, le, If,Ig, Ih or Ii, preferably as in formula I,

and their physiologically tolerable salts.

In addition, preferred compounds of the formula I are those in which theradicals R(1), R(2), R(3), R(4) and R(5) are as defined above and theradicals R(4) and R(5) as in the formula Ij are linked to the biphenylsubstituent

and their physiologically tolerable salts.

Alkyl radicals and alkylene radicals can be straight-chain or branched.This also applies to the alkylene radicals of the formulae C_(a)H_(2a),C_(b)H_(2b), C_(d)H_(2d), C_(g)H_(2g) and C_(l)H_(2l). Alkyl radicalsand alkylene radicals can also be straight-chain or branched if they aresubstituted or are contained in other radicals, e.g. in an alkoxyradical or in an alkylmercapto radical or in a fluorinated alkylradical.

Cycloalkyl is also understood as meaning alkyl-substituted rings.

Examples of alkyl radicals having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atomsare: methyl, ethyl, n-propyl, n-butyl, pentyl, hexyl, heptyl, octyl,isopropyl, isobutyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl,sec-butyl, tert-butyl, tert-pentyl. The divalent radicals derived fromthese radicals, e.g. methylene, 1,1-ethylene, 1,2-ethylene,1,1-propylene, 1,2-propylene, 2,2-propylene, 1,3-propylene,1,4-butylene, 1,5-pentylene, 2,2-dimethyl-1,3-propylene, 1,6-hexylene,etc. are examples of alkylene radicals.

Cycloalkyl radicals having 3, 4, 5, 6 or 7 carbon atoms are inparticular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, which, however, can also be substituted, for example, byalkyl having 1, 2, 3 or 4 carbon atoms. Examples of substitutedcycloalkyl radicals which may be mentioned are 4-methylcyclohexyl and2,3-dimethylcyclopentyl.

Heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms is understoodas meaning in particular radicals which are derived from phenyl ornaphthyl, in which one or more CH groups are replaced by N and/or inwhich at least two adjacent CH groups are replaced by S, NH or O (withformation of a five-membered aromatic ring). In addition, one or bothatoms of the condensation site of bicyclic radicals (such as inindolizinyl) can also be nitrogen atoms.

Heteroaryl is in particular furanyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl,indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl,quinazolinyl, cinnolinyl. N-Containing heterocycles having 1, 2, 3, 4,5, 6, 7, 8 or 9 carbon atoms are in particular the aromatic systems 1-,2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4-or 5-pyrazolyl,1,2,3-triazol-1-, -4- or 5-yl, 1,2,4-triazol-1, -3- or -5-yl, 1- or5-tetrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl,1,2,3-oxadiazol-4- or 5-yl, 1,2,4-oxadiazol-3- or 5-yl,1,3,4-oxadiazol-2-yl or -5-yl, 2-, 4- or 5-thiazolyl, 3-, 4- or5-isothiazolyl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3-or-5-yl, 1,2,3-thiadiazol-4- or 5-yl, 2-, 3- or 4-pyridyl, 2-, 4-, 5-or6-pyrimidinyl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or7-indazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-,7- or 8-isoquinolyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-,6-, 7- or 8-cinnolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 1-, 4-,5-, 6-, 7- or 8-phthalazinyl.

The N-containing heterocycles pyrrolyl, imidazolyl, quinolyl, pyrazolyl,pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl are particularlypreferred. Thienyl is both 2- and 3-thienyl. Furyl is 2- and 3-furyl.

Monosubstituted phenyl radicals can be substituted in the 2-, the 3- orthe 4-position, disubstituted in the 2,3-, 2,4-, 2,5-, 2,6-, 3,4 or3,5-position, trisubstituted in the 2,3,4-, 2,3,5-, 2,3,6- 2,4,5-,2,4,6- or 3,4,5-position. The same correspondingly applies analogouslyto the N-containing heterocycles or the thiophene radical. In the caseof di- or trisubstitution of a radical, the substituents can beidentical or different.

If the compounds of the formula I contain one or more acidic or basicgroups or one or more basic heterocycles, the invention also relates tothe corresponding physiologically or toxicologically tolerable salts, inparticular the pharmaceutically utilizable salts. Thus the compounds ofthe formula I which carry acidic groups, e.g. one or more COOH groups,can be used, for example, as alkali metal salts, preferably sodium orpotassium salts, or as alkaline earth metal salts, e.g. calcium ormagnesium salts, or as ammonium salts, e.g. as salts with ammonia ororganic amines or amino acids. Compounds of the formula I which carryone or more basic, i.e. protonatable, groups or contain one or morebasic heterocyclic rings can also be used in the form of theirphysiologically tolerable acid addition salts with inorganic or organicacids, for example as hydrochlorides, phosphates, sulfates,methanesulfonates, acetates, lactates, maleates, fumarates, malates,gluconates etc.

If the compounds of the formula I simultaneously contain acidic andbasic groups in the molecule, the invention also includes, in additionto the salt forms described, internal salts, so-called betaines. Saltscan be obtained from the compounds of the formula I by customaryprocesses, for example by combination with an acid or base in a solventor dispersant or alternatively from other salts by anion exchange.Physiologically tolerable salts of compounds of the formula (I) are alsounderstood as meaning, for example, organic and inorganic salts, such asare described in Remington's Pharmaceutical Sciences (17th edition,pages 1418 (1985)). On account of the physical and chemical stabilityand the solubility, sodium, potassium, calcium and ammonium salts, interalia, are preferred for acidic groups; salts of hydrochloric acid,sulfuric acid, phosphoric acid or of carboxylic acids or sulfonic acids,such as, for example, acetic acid, citric acid, benzoic acid, maleicacid, fumaric acid, tartaric acid and p-toluenesulfonic acid, interalia, are preferred for basic groups.

If appropriately substituted, the compounds of the formula I can bepresent in stereoisomeric forms. If the compounds of the formula Icontain one or more asymmetric centers, these can independently of oneanother have the S configuration or the R configuration. The inventionincludes all possible stereoisomers, e.g. enantiomers or diastereomers,and mixtures of two or more stereoisomeric forms, e.g. enantiomersand/or diastereomers, in any desired ratios. The invention thus relatesto, for example, enantiomers in enantiomerically pure form, both aslevo- and dextrorotatory antipodes, and in the form of mixtures of thetwo enantiomers in different ratios or in the form of racemates. In thecase of the presence of cis/trans isomerism, the invention relates bothto the cis form and the trans form and mixtures of these forms. Ifdesired, the individual stereoisomers can be prepared by resolution of amixture according to customary methods or, for example, bystereoselective synthesis. In the case of the presence of mobilehydrogen atoms, the present invention also includes all tautomeric formsof the compounds of the formula I.

The invention also relates to a process for the preparation of thecompounds of the formula I, and their physiologically tolerable salts,which comprises reacting a compound of the formula II

in which the radicals are as defined above and which, analogously to J.Med. Chem. 1995, 38, 2357 can be prepared in a manner known per se, withcyanogen bromide. The reaction is advantageously carried out in adipolar aprotic solvent which is stable to cyanogen bromide, for exampleacetonitrile, DMA, TMU or NMP, using a strong auxiliary base which isnot very nucleophilic, such as, for example, K₂CO₃ or Cs₂CO₃. A suitablereaction temperature is a temperature from 0° C. to the boiling point ofthe solvent used; a temperature from 60° C. to 120° C. is preferred.

The introduction of the substituents R(2) or R(3) equal to alkoxyalkoxyis carried out by nucleophilic aromatic substitution on compounds of theformula II where R(2) is equal to a nucleofugic leaving group,preferably F, Cl or Br and R(3) is equal to formyl or on compounds ofthe formula II where R(3) is equal to a nucleofugic leaving group,preferably F, Cl or Br and R(2) is equal to formyl. The nucleophileemployed is advantageously an alkali metal salt of the alcoholconcerned, the sodium, potassium or cesium salt is preferred, in thealcohol concerned as a solvent. The reaction temperature is atemperature between 0° C. and the boiling point of the alcohol; atemperature between 40° C. and the boiling point of the alcohol ispreferred.

The introduction of the substituents R(2) or R(3) equal tobis(alkoxyalyl)amino is carried out by nucleophilic aromaticsubstitution on compounds of the formula II where R(2) is equal to anucleofugic leaving group, preferably F, Cl or Br and R(3) is equal toformyl or on compounds of the formula II where R(3) is equal to anucleofugic leaving group, preferably F, Cl or Br and R(2) is equal toformyl. The nucleophile employed is either the bis(alkoxyalyl)amineconcerned or an alkali metal salt of the amine concerned, the lithiumsodium, potassium or cesium salt is preferred, in a dipolar aproticsolvent. Suitable solvents are therefore THF, DMF, tetramethylurea,N-methylpyrrolidone and hexamethylphosphoramide. The reactiontemperature is a temperature between 0° C. and the boiling point of thesolvent; a temperature between 40° C. and the boiling point of thesolvent is preferred.

The introduction of the substituent R(4) is advantageously carried outat the stage of the toluene derivative III

where Hal is a leaving group compatible with the Suzuki reaction,preferably bromine or iodine. The introduction of an SO₂-alkyl radicalby means of chlorosulfonation is described by way of example in J. Med.Chem. 1997, 40, 2017 or J. Org. Chem. (1991), 56(16), 4974-6.

All reactions for the synthesis of the compounds of the formula I arewell known per se to the person skilled in the art and can be carriedout under standard conditions according to or analogously to literatureprocedures, such as are described, for example, in Houben-Weyl, Methodender organischen Chemie [Methods of organic chemistry], Thieme-Verlag,Stuttgart, or Organic Reactions, John Wiley & Sons, New York. Dependingon the conditions in the individual case, it may also be advantageous ornecessary in the synthesis of the compounds of the formula I, in orderto avoid side reactions, to block certain functional groups temporarilyby the introduction of protective groups and later to then release themagain or to employ functional groups first in the form of precursorsfrom which the desired functional group is generated in a later step.Such synthesis strategies and the protective groups or precursorssuitable for the individual case are known to the person skilled in theart. The compounds of the formula I obtained can optionally be purifiedby customary purification methods, for example by recrystallization orchromatography. The starting compounds for the preparation of thecompounds of the formula I are commercially obtainable or can beprepared by or analogously to literature procedures.

In addition, the invention relates to the use of a compound of theformula I and/or of a physiologically tolerable salt thereof for theproduction of a medicament for the treatment or prophylaxis of illnessescaused by ischemic conditions;

and also the use of a compound of the formula I and/or of aphysiologically tolerable salt thereof for the production of amedicament for the treatment or prophylaxis of cardiac infarct;

and also the use of a compound of the formula I and/or of aphysiologically tolerable salt thereof for the production of amedicament for the treatment or prophylaxis of angina pectoris;

and also the use of a compound of the formula I and/or of aphysiologically tolerable salt thereof for the production of amedicament for the treatment or prophylaxis of ischemic conditions ofthe heart;

and also the use of a compound of the formula I and/or of aphysiologically tolerable salt thereof for the production of amedicament for the treatment or prophylaxis of ischemic conditions ofthe peripheral and central nervous system and of stroke;

and also the use of a compound of the formula I and/or of aphysiologically tolerable salt thereof for the production of amedicament for the treatment or prophylaxis of ischemic conditions ofperipheral organs and limbs;

and also the use of a compound of the formula I and/or of aphysiologically tolerable salt thereof for the production of amedicament for the treatment of states of shock;

and also the use of a compound of the formula I and/or of aphysiologically tolerable salt thereof for the production of amedicament for use in surgical operations and organ transplantation;

and also the use of a compound of the formula I and/or of aphysiologically tolerable salt thereof for the production of amedicament for the preservation and storage of transplants for surgicalmeasures;

and also the use of a compound of the formula I and/or of aphysiologically tolerable salt thereof for the production of amedicament for the treatment of illnesses in which cell proliferation isa primary or secondary cause; and thus their use for the production ofan antiatherosclerotic, an agent against diabetic late complications,carcinomatous disorders, fibrotic disorders such as pulmonary fibrosis,hepatic fibrosis or renal fibrosis, or prostate hyperplasia;

and also the use of a compound of the formula I and/or of aphysiologically tolerable salt thereof for the production of amedicament for the treatment of impaired respiratory drive;

and also a pharmaceutical preparation which comprises an efficaciousamount of a compound of the formula I and/or of a physiologicallytolerable salt thereof.

The compounds of the formula I according to the invention are suitableas inhibitors of the sodium-dependent bicarbonate/chloride exchanger(NCBE) or of the sodium/bicarbonate symporter.

Compounds similar to the compounds of the formula I according to theinvention are disclosed in U.S. Pat. Nos. 5,482,957 and 5,604,251.However, they do not have the sulfonylcyanamide side chain which isalways present according to the invention. Imidazole derivatives asangiotensin II antagonists are also described in WO9523792, WO9523791,U.S. Pat. No. 5,391,732, EP-A 648763. The known compounds areangiotensin II receptor antagonists of the subtype AT1, which action isnot present or only present to a small extent in the compounds Iaccording to the invention.

In the earlier European Patent Application EP-A 855392, imidazolederivatives having a biphenylsulfonylcyanamide side chain are proposedas NCBE inhibitors. The novel imidazole derivatives having abiphenylsulfonylcyanamide side chain described in the present inventionhave a specific substituent R(2) and/or R(3) on the imidazole ring andare distinguished by a high efficacy in the inhibition of the cellularNa⁺-dependent bicarbonate/chloride exchange as well as an improvedbioavailability.

The compounds of the formula (I) according to the invention exhibit verygood antiarrhythmic properties, such as are important, for example, forthe treatment of illnesses which occur in the case of oxygen deficiencysymptoms. Because of their pharmacological properties, the compounds ofthe formula (I) are outstandingly suitable as antiarrhythmicpharmaceuticals having a cardioprotective component for infarctprophylaxis and infarct treatment and also for the treatment of anginapectoris, where they also preventively inhibit or greatly decrease thepathophysiological processes in the formation of ischemically induceddamage, in particular in the elicitation of ischemically induced cardiacarrhythmias. Because of their protective actions against pathologicalhypoxic and ischemic situations, the compounds of the formula (I)according to the invention can be used, as a result of inhibition of thecellular Na⁺-dependent Cl⁻/HCO₃ ⁻ exchange mechanism (NCBE) or of thesodium/bicarbonate symporter, as a pharmaceutical for the treatment ofall acute or chronic damage caused by ischemia or illnesses inducedprimarily or secondarily thereby. They protect organs which have anacutely or chronically deficient supply of oxygen by reducing orpreventing ischemically induced damage and are thus suitable aspharmaceuticals, for example in thromboses, vasospasms, atherosclerosisor in surgical interventions (e.g. in organ transplantation of thekidney and liver where the compounds can be used both for the protectionof the organs in the donor before and during removal, for the protectionof removed organs, for example, during treatment with or storage thereofin physiological bath fluids, and also during transfer to therecipient's body) or chronic or acute kidney failure.

The compounds of the formula (I) are also valuable pharmaceuticalshaving a protective action when carrying out angioplastic surgicalinterventions, for example on the heart and also on peripheral vessels.Corresponding to their protective action against ischemically induceddamage, the compounds are also suitable as pharmaceuticals for thetreatment of ischemias of the nervous system, in particular of the CNS,where they are suitable, for example, for the treatment of stroke or ofcerebral edema.

Moreover, the compounds of the formula (I) according to the inventionare also suitable for the treatment of forms of shock, such as, forexample, of allergic, cardiogenic, hypovolemic and of bacterial shock.

Moreover, the compounds of the formula (I) according to the inventionare distinguished by strong inhibitory action on the proliferation ofcells, for example fibroblast cell proliferation and the proliferationof the vascular smooth muscle cells and of the mesangium cells.Therefore the compounds of the formula (I) are suitable as valuabletherapeutics for illnesses in which cell proliferation is a primary orsecondary cause, and can therefore be used as antiatherosclerotics,agents against diabetic late complications, carcinomatous disorders,fibrotic disorders such as pulmonary fibrosis, hepatic fibrosis or renalfibrosis, organ hypertrophs and/or hyperplasia, in particular inprostate hyperplasia or prostate hypertrophy.

The compounds of the formula I according to the invention and theirphysiologically tolerable salts are suitable for use in the therapyand/or propylaxis of cardiacinfarct, of angina pectoris, of illnessescaused by ischemic conditions, of disturbed respiratory drive, ofischemic conditions of the heart, of ischemic conditions of theperipheral and central nervous system and of stroke, of ischemicconditions of peripheral organs and limbs, of illnesses in which cellproliferation is a primary or secondary cause, or in the treatment ofstates of shock, or for use in surgical operations and organtransplantation or for the preservation and storage of transplants forsurgical measures.

It was found that inhibitors of the Na⁺-dependent Cl⁻/HCO₃ ⁻ exchanger(NCBE inhibitors) or of the sodium/bicarbonate symporter can stimulatethe respiration by an increase in the chemosensitivity of therespiratory chemoreceptors. These chemoreceptors are responsible to aconsiderable extent for the maintenance of an ordered respiratoryactivity. They are activated by hypoxia, pH decrease and rise in CO₂(hypercapnia) in the body and lead to an adjustment of the respiratoryminute volume. During sleep, the respiration is particularly susceptibleto disturbance and is dependent to a great extent on the activity of thechemoreceptors. Improvement in the respiratory drive by stimulation ofthe chemoreceptors with substances which inhibit Na⁺-dependent Cl⁻/HCO₃⁻ exchange leads to an improvement in the respiration in the followingclinical conditions and illnesses: disturbed central respiratory drive(e.g. central sleep apnea, cot death, postoperative hypoxia),muscle-related respiratory disorders, respiratory disorders afterlong-term ventilation, respiratory disorders during adaptation in a highmountain region, obstructive and mixed forms of sleep apneas, acute andchronic lung diseases with hypoxia and hypercapnia.

The compounds of the formula I according to the invention and theirphysiologically tolerable salts can be used in animals, preferably inmammals, and in particular in humans, as pharmaceuticals on their own,as mixtures with one another or in the form of pharmaceuticalpreparations. The present invention also relates to the compounds of theformula I and their physiologically tolerable salts for administrationas pharmaceuticals, their use in the therapy and prophylaxis of thesyndromes mentioned and their production of medicaments therefor. Thepresent invention furthermore relates to pharmaceutical preparationswhich as active constituent contain an efficacious dose of at least onecompound of the formula I and/or of a physiologically tolerable saltthereof in addition to customary pharmaceutically innocuous vehicles andexcipients. The pharmaceutical preparations normally contain 0.1 to 99percent by weight, preferably 0.5 to 95 percent by weight, of thecompounds of the formula I and/or their physiologically tolerable salts.The pharmaceutical preparations can be produced in a manner known perse. For this, the compounds of the formula I and/or theirphysiologically tolerable salts are brought, together with one or moresolid or liquid pharmaceutical vehicles and/or excipients and, ifdesired, in combination with other pharmaceutical active compounds, intoa suitable administration form or dose form, which can then be used as apharmaceutical in human or veterinary medicine.

Pharmaceuticals which contain a compound of the formula (I) and/or itsphysiologically tolerable salts can in this case be administered orally,parenterally, intravenously, rectally or by inhalation, the preferredmanner of administration being dependent on the particular symptoms ofthe disorder. The compounds of the formula I can in this case be used ontheir own or together with pharmaceutical auxiliaries, namely both inveterinary and in human medicine.

Auxiliaries which are suitable for the desired pharmaceuticalformulation are familar to the person skilled in the art on the basis ofhis expert knowledge. Beside solvents, gel-forming agents, suppositorybases, tablet auxiliaries, and other vehicles, it is possible to use,for example, antioxidants, dispersants, emulsifiers, antifoams, flavorcorrigents, preservatives, solubilizers or colorants.

For an oral administration form, the active compounds are mixed with theadditives suitable therefor, such as excipients, stabilizers or inertdiluents, and brought by the customary methods into the suitableadministration forms, such as tablets, coated tablets, hard capsules,aqueous, alcoholic or oily solutions. Inert excipients which can be usedare, for example, gum arabic, magnesia, magnesium carbonate, potassiumphosphate, lactose, glucose or starch, in particular corn starch. Inthis case, the preparation can be realized both as dry and as moistgranules. Suitable oily excipients or solvents are, for example,vegetable or animal oils, such as sunflower oil or cod liver oil.

For subcutaneous or intravenous administration, the active compounds, ifdesired with the substances customary therefor such as solubilizers,emulsifiers or further auxiliaries, are brought into solution,suspension or emulsion. Possible solvents are, for example: water,physiological saline solution or alcohols, e.g. ethanol, propanol,glycerol, and in addition also sugar solutions such as glucose ormannitol solutions, or alternatively a mixture of the various solventsmentioned.

Suitable pharmaceutical formulations for administration in the form ofaerosols or sprays are, for example, solutions, suspensions or emulsionsof the active compound of the formula I in a pharmaceutically acceptablesolvent, such as, in particular, ethanol or water, or a mixture of suchsolvents.

If required, the formulation can also contain other pharmaceuticalauxiliaries such as surfactants, emulsifiers and stabilizers and also apropellant gas. Such a preparation contains the active compoundcustomarily in a concentration from approximately 0.1 to 10, inparticular from approximately 0.3 to 3, % by weight.

The dose of the active compound of a compound of the formula (I) to beadministered and the frequency of administration depend on the potencyand duration of action of the compounds used; additionally also on thenature and severity of the illness to be treated and on the sex, age,weight and individual responsiveness of the mammal to be treated. Onaverage, the daily dose of a compound of the formula I in the case of apatient weighing approximately 75 kg is at least 0.001 mg/kg, preferably0.01 mg/kg, to at most 10 mg/kg, preferably 1 mg/kg, of body weight. Inthe case of acute episodes of the illness, for example immediately aftersuffering a cardiac infarct, higher and especially more frequent dosesmay also be necessary, e.g. up to 4 individual doses per day. Inparticular in the case of i.v. administration, for example in the caseof an infarct patient in the intensive care unit, up to 200 mg per daymay be necessary.

The compounds of the formula I and/or their physiologically tolerablesalts can also be employed to achieve an advantageous therapeuticaction, together with other pharmacologically active compounds, for thetreatment or prophylaxis of the abovementioned symptoms, in particularfor the treatment of cardiovascular disorders. Combination withinhibitors of the sodium/hydrogen exchanger (NHE) and/or with activesubstances from other classes of cardiovascular active compound ispreferred.

The invention additionally relates to the combination of a) NCBEinhibitors of the formula I and/or their physiologically tolerable saltswith NHE inhibitors and/or their physiologically tolerable salts; b)NCBE inhibitors of the formula I and/or their physiologically tolerablesalts with active substances from other classes of cardiovascular activecompound and/or their physiologically tolerable salts and also c) ofNCBE inhibitors of the formula I and/or their physiologically tolerablesalts with NHE inhibitors and/or their physiologically tolerable saltsand with active substances from other classes of cardiovascular activecompound and/or their physiologically tolerable salts.

The active compounds which are known and identified as NHE inhibitorsare guanidine derivatives, preferably acylguanidines, inter alia such asare described in Edward J. Cragoe, Jr., “DIURETICS, Chemistry,Pharmacology and Medicine”, J. WILEY & Sons (1983), 303-341 or the NHEinhibitors mentioned in DE19737224.4.

Suitable NHE inhibitors are, for example, also benzoylguanidines such asare described in U.S. Pat. Nos. 5,292,755, 5,373,024, 5,364,868,5,591,754, 5,516,805, 5,559,153, 5,571,842, 5,641,792, 5,631,293, EP-A577024, EP-A 602522, EP-A 602523, EP-A 603650, EP-A 604852, EP-A 612723,EP-A 627413, EP-A 628543, EP-A 640593, EP-A 640588, EP-A 702001, EP-A713864, EP-A 723956, EP-A 754680, EP-A 765868, EP-A 774459, EP-A 794171,EP-A 814077, EP-A 869116; ortho-substituted benzoylguanidines, such asare described in EP-A 556673, EP-A 791577, EP-A 794172;ortho-amino-substituted benzoylguanidines, such as are described in EP-A690048; isoquinolines, such as are described in EP-A 590455; benzo-fused5-membered ring heterocycles, such as are described in EP-A 639573;diacyl-substituted guanidines, such as are described in EP-A 640587;acylguanidines, such as are described in U.S. Pat. No. 5,547,953;phenyl-substituted alkyl- or alkenylcarboxylic acid guanidines bearingperfluoroalkyl groups, such as are described in U.S. Pat. No. 5,567,734,EP-A 688766; heteroaroylguanidines, such as are described in EP-A676395; bicyclic heteroaroylguanidines, such as are described in EP-A682017; indenoylguanidines, such as are described in EP-A 738712;benzyloxycarbonylguanidines, such as are described in EP-A 748795;phenyl-substituted alkenylcarboxylic acid guanidines bearingfluorophenyl groups, such as are described in EP-A 744397; substitutedcinnamoylguanidines, such as are described in EP-A 755919;sulfonimidamides, such as are described in EP-A 771788;benzenedicarboxylic acid diguanidines, such as are described in EP-A774458, EP-A 774457; diarylcarboxylic acid diguanidines, such as aredescribed in EP-A 787717; substituted thiophenylalkenylcarboxylic acidguanidines, such as are described in EP-A 790245; bis-ortho-substitutedbenzoylguanidines, such as are described in EP-A 810207; substituted 1or 2-naphthylguanidines, such as are described in EP-A 810205 and EP-A810206; indanylideneacetylguanidines, such as are described in EP-A837055; phenyl-substituted alkenylcarboxylic acid guanidines such as aredescribed in EP-A 825178; aminopiperidylbenzoylguanidines, such as aredescribed in EP-A 667341; heterocycloxybenzylguanidines, such as aredescribed in EP-A 694537; ortho-substituted benzoylguanidines, such asare described in EP-A 704431; ortho-substituted alkylbenzylguanidines,such as are described in EP-A 699660; ortho-substitutedheterocyclylbenzoylguanidines, such as are described in EP-A 699666;ortho-substituted 5-methylsulfonylbenzoylguanidines, such as aredescribed in EP-A 708088; ortho-substituted5-alkylsulfonylbenzoylguanidines having 4-amino substituents, such asare described in EP-A 723963; ortho-substituted5-alkylsulfonylbenzoylguanidines having 4-mercapto substituents, such asare described in EP-A 743301; 4-sulfonyl or 4-sulfinylbenzylguanidines,such as are described in EP-A 758644; alkenylbenzoylguanidines, such asare described in EP-A 760365; benzoylguanidines having fused, cyclicsulfones, such as are described in DE 19548708; benzoyl-, polycyclicaroyl- and heteroaroylguanidines, such as are described in WO 9426709;3-aryl/heteroarylbenzoylguanidines, such as are described in WO 9604241;3-phenylbenzoylguanidines having a basic amide in the 5-position, suchas are described in WO 9725310; 3-dihalothienyl- or3-dihalophenylbenzoylguanidines having a basic substituent in the5-position, such as are described in WO 9727183;3-methylsulfonylbenzoylguanidines having certain amino substituents inthe 4-position, such as are described in WO 9512584; amiloridederivatives, such as are described in WO 9512592;3-methylsulfonyl-benzoylguanidines having certain amino substituents inthe 4-position, such as are described in WO 9726253; indoloylguanidines,such as are described in EP-A 622356 and EP-A 708091; indoloylguanidineshaving a fused additional ring system, such as are described in EP787728; methylguanidine derivatives, such as are described in WO9504052; 1,4-benzoxazinoylguanidines, such as are described in EP-A719766; 5-bromo-2-naphthoylguanidines, such as are described in JP8225513; quinoline-4-carbonylguanidines having a phenyl radical in the2-position, such as are described in EP-A 726254; cinnamoylguanidines,such as are described in JP 09059245; propenoylguanidines having anaphthalene substituent, such as are described in JP 9067332;propenoylguanidines having indole substituents, such as are described inJP 9067340; or heteroaryl-substituted acroylguanidines, such as aredescribed in WO 9711055, and their physiologically tolerable salts.

Preferred NHE inhibitors are the compounds emphasized as preferred inthe publications mentioned. Very particularly preferred compounds arecariporide (HOE642), HOE 694, EMD 96785, FR 168888, FR 183998, SM-20550,KBR-9032, and their physiologically tolerable salts. Most preferred iscariporide or another physiologically tolerable salt ofN-(4-isopropyl-3-methanesulfonylbenzoyl)guanidine.

Examples of classes of active compounds having cardiovascular activitywhich can therapeutically be combined advantageously with NCBEinhibitors or can additionally be combined with combinations of NCBEinhibitors and NHE inhibitors are beta-receptor blockers, calciumantagonists, angiotensin-converting enzyme inhibitors, angiotensinreceptor blockers, loop diuretics, thiazide diuretics, potassium-sparingdiuretics, aldosterone antagonists, such as are employed, for example,in lowering of the blood pressure, and also cardiac glycosides or otheragents increasing the contractile force in the treatment of cardiacinsufficiency and of congestive heart failures, and also antiarrhythmicsof the classes I-IV, nitrates, KATP openers, KATP blockers, inhibitorsof the veratridine-activatable sodium channel, etc. For example, thefollowing are thus suitable: the beta-blockers propanolol, atenolol,metoprolol; the calcium antagonists diltiazem hydrochloride, verapamilhydrochloride, nifedipine; the ACE inhibitors captopril, enalapril,ramipril; trandolapril, quinapril, spirapril, preferably ramipril ortrandolapril; the angiotensin II receptor antagonists losartan,valsartan, telmisartan, eprosartan, tasosartan, candesartan, irbesartan;the loop diuretics furosemide, piretanide, torasemide; the thiazidediuretics hydrochlorothiazide, metolazone, indapamide; thepotassium-sparing diuretics amiloride, triamterene, spironolactone; thecardiac glycosides digoxin, digitoxin, strophanthin; the antiarrhythmicsamiodarone, sotalol, bretylium, flecainide; the nitrate glyceroltrinitrate; the K⁺(ATP) openers cromakalim, lemakalim, nocorandil,pinacidil, minoxidil; the inhibitors of the veratridine-activatable Na⁺channel. An example of such a particularly advantageous combinationcomponent with NCBE inhibitors are blockers of the non-inactivatingsodium channel (veratridine-activatable sodium channel). Thecombinations of an NCBE inhibitor with a blocker of the non-inactivatingsodium channel (veratridineactivatable sodium channel) are suitable forinfarct and reinfarct prophylaxis and infarct treatment and also for thetreatment of angina pectoris and the inhibition of ischemically inducedcardiac arrhythmias, tachycardia and the formation and maintenance ofventricular fibrillation, the combinations of an NCBE inhibitor with ablocker of the non-inactivating sodium channel also preventivelyinhibiting or greatly decreasing the pathophysiological processes in theformation of ischemically induced damage. Because of their enhancedprotective actions against pathological hypoxic and ischemic situations,the combinations according to the invention of an NCBE inhibitor with ablocker of the non-inactivating sodium channel can be used, as a resultof enhanced inhibition of the Na⁺ influx into the cell, aspharmaceuticals for the treatment of all acute or chronic damage inducedby ischemia or diseases induced primarily or secondarily thereby. Thisrelates to their use as pharmaceuticals for surgical interventions, e.g.in organ transplantation, where the combinations of an NCBE inhibitorwith a blocker of the non-inactivating sodium channel can be used bothfor the protection of the organs in the donor before and during removal,for the protection of removed organs, for example, also during storagethereof in physiological bath fluids, and also during transfer to therecipient's body. The combinations of an NCBE inhibitor with a blockerof the non-inactivating sodium channel are likewise valuable,protectively acting pharmaceuticals when carrying out angioplasticsurgical interventions, for example on the heart, and also on peripheralvessels. In accordance with their protective action against ischemicallyinduced damage, the combinations of an NCBE inhibitor with a blocker ofthe noninactivating sodium channel are also suitable as pharmaceuticalsfor the treatment of ischemias of the nervous system, in particular ofthe central nervous system, where they are suitable for the treatment ofstroke or of cerebral edema. Moreover, the combinations according to theinvention of an NCBE inhibitor with a blocker of the non-inactivatingsodium channel are also suitable for the treatment of forms of shock,such as, for example, of allergic, cardiogenic, hypovolemic andbacterial shock.

Beside administration as a fixed combination, the invention also relatesto the simultaneous, separate or sequential administration of NCBEinhibitors of the formula I and/or their physiologically tolerable saltswith NHE inhibitors and/or an additional active substance from anotherclass of cardiovascular active compound for the treatment of theabovementioned diseases.

The invention additionally relates to a pharmaceutical preparationcomprising a) an NCBE inhibitor of the formula I and/or theirphysiologically tolerable salt and an NHE inhibitor and/or theirphysiologically tolerable salts; or b) an NCBE inhibitor of the formulaI and/or their physiologically tolerable salt and additionally an activesubstance from another class of cardiovascular active compound and/ortheir physiologically tolerable salts; or c) an NCBE inhibitor of theformula I and/or its physiologically tolerable salt, an NHE inhibitorand additionally an active substance from another class ofcardiovascular active compound, and/or its physiologically tolerablesalts.

By combined administration, the effect of one combination component canbe potentiated by the respective other component, i.e. the action and/orduration of action of a combination or preparation according to theinvention is stronger or longer-lasting than the action and/or theduration of action of the respective individual components (synergisticeffect). In the case of combined administration, this leads to alowering of the dose of the respective combination components, comparedwith individual administration. The combinations and preparationsaccording to the invention accordingly have the advantage that theamounts of active compound to be administered can be significantlyreduced and undesirable side effects can be eliminated or greatlyreduced.

The invention furthermore relates to a commercial pack, comprising aspharmaceutical active compound a) an NCBE inhibitor of the formula I andan NHE inhibitor and/or their physiologically tolerable salts; or b) anNCBE inhibitor of the formula I and additionally an active substancefrom another class of cardiovascular active compound and/or theirphysiologically tolerable salts; or c) an NCBE inhibitor of the formulaI, an NHE inhibitor and additionally an active substance from anotherclass of cardiovascular active compound and/or their physiologicallytolerable salts, in each case together with instructions for the use ofthese active compounds in combination for simultaneous, separate orsequential administration in the treatment or prophylaxis of theabovementioned syndromes, in particular for the treatment ofcardiovascular disorders.

The pharmaceutical preparations according to the invention can beprepared, for example, by either intensively mixing the individualcomponents as powders, or by dissolving the individual components in thesuitable solvents such as, for example, a lower alcohol and thenremoving the solvent.

The weight ratio of NBCE inhibitor to the NHE inhibitor or the substancehaving cardiovascular activity in the combinations and preparationsaccording to the invention is expediently 1:0.01 to 1:100, preferably1:0.1 to 1:10.

The combination and preparations according to the invention contain atotal of preferably 0.5-99.5% by weight, in particular 4-99% by weight,of these active compounds.

When used according to the invention in mammals, preferably in humans,the doses of the various active compound components vary, for example,in the range from 0.001 to 100 mg/kg/day.

List of abbreviations:

BCECF 2′,7′-Bis(2-carboxyethyl)-5,6-carboxyfluorescein CH₂Cl₂Dichloromethane DCI Desorption-chemical ionization DMFN,N-Dimethylformamide EA Ethyl acetate (EtOAc) El Electron impact ESElectrospray ionization HEP n-Heptane MeOH Methanol mp Melting pointNCBE sodium-dependent chloride/bicarbonate exchanger NHE Sodium/hydrogenexchanger RT Room temperature CNS Central nervous system

General Procedure for the Preparation of Sulfonylcyanamides fromSulfonamides

The sulfonamide starting material is dissolved in 10 ml/mmol ofanhydrous acetonitrile, 3 mol equivalents of K₂CO₃ and one molequivalent of a 5 N solution of BrCN in acetonitrile are added dropwiseand the mixture is heated under reflux until conversion is complete(typical reaction time 10 minutes to 6 hours). The reaction mixture isthen chromatographed on silica gel without further working up.

EXAMPLES Example 14′-[5-Formyl-4-(2-methoxyethoxy)-2-phenylimidazol-1-ylmethyl]-3′-methanesulfonylbiphenyl-2-sulfonylcyanamide

a) 2-Bromo-5-methylbenzenesulfonyl chloride

40 g of 4-bromotoluene are slowly introduced into 250 ml ofchlorosulfonic acid at −10° C. with stirring. The mixture is stirred atthis temperature for 30 minutes, allowed to warm to 0° C. and pouredonto excess ice. The product is filtered off with suction and washedwith a little water. It is dried over P₄O₁₀ in vacuo and 63 g of acolorless solid are obtained, which is directly reacted further.

b) 2-Bromo-5-methylbenzenesulfinic acid

37.6 g of sodium sulfite are dissolved in 500 ml of water and heated to70° C. 62 g of 2-bromo-5-methylbenzenesulfonyl chloride are added inportions at this temperature. A 10 N aqueous NaOH solution issimultaneously added dropwise here so that the pH of the solution iskept between pH=9 and pH=10. The mixture is stirred at 70° C. for 1.5hours, and the solution is filtered off and subsequently adjusted topH=0 in an ice bath using a saturated aqeuous HCl solution. The mixtureis stirred for 30 minutes, then the product is filtered off,subsequently washed with a little water and dried. 49.6 g of whitecrystals are obtained, mp 120-122° C. MS (ES): 236 (M+H)⁺

c) Sodium 2-bromo-5-methylbenzenesulfinate

49.6 g of 2-bromo-5-methylbenzenesulfinic acid are dissolved in 400 mlof methanol and treated with an equimolar amount of NaOH in 50 ml ofwater. The mixture is stirred at RT for 3 hours, the solution isfiltered off and subsequently the solvents are removed in vacuo.Finally, water residues are removed azeotropically with 50 ml oftoluene. The solid residue is dried over P₄O₁₀ in vacuo and 54.0 g ofproduct are obtained, mp 288-290° C. (with decomposition).

d) 1-Bromo-2-methanesulfonyl-4-methylbenzene

54.0 g of sodium 2-bromo-5-methylbenzenesulfinate are suspended in 300ml of anhydrous DMF and treated with 45.7 ml of methyl iodide. Thetemperature of the solution rises to 50° C. in the course of this. Themixture is stirred at 50° C. for 3 hours and the DMF is removed invacuo. The residue is stirred with 500 ml of water, subsequently stirredat 0° C. for 1 hour and filtered off. The product is washed with water,dried and recrystallized from 400 ml of HEP/250 ml of EA using activecarbon. 27.0 g of colorless crystals are obtained, mp 110-114° C.

R_(f)(EA/HEP 1:4)=0.09 MS (DCI): 250 (M+H)⁺

e) 1-Bromo-4-bromomethyl-2-methanesulfonylbenzene

9.9 g of 1-bromo-2-methanesulfonyl-4-methylbenzene are taken up in 100ml of chlorobenzene, 77 mg of benzoyl peroxide and 7.1 g ofN-bromosuccinimide are added and the mixture is refluxed for 1 hour. Thesolvent is then removed in vacuo, the residue is taken up in 100 ml ofCH₂Cl₂ and the mixture is washed twice with 50 ml of a saturated aqueousNa₂CO₃ solution and once with 50 ml of water. It is dried over Na₂SO₄and the solvent is removed in vacuo. The residue is recrystallized from80 ml of HEP/30 ml of EA and 6.9 g of a pale yellow solid are obtained,mp 120-124° C.

R_(f)(EA/HEP 1:2)=0.38 MS (DCI): 329 (M+H)⁺

f)3-(4-Bromo-3-methanesulfonylbenzyl)-5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde

1.0 g of 5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde (Chem. Pharm.Bull. 1976, 24(5), 960), 1.6 g of1-bromo-4-bromomethyl-2-methanesulfonylbenzene and 691 mg of K₂CO₃ arestirred at RT for 18 hours in 25 ml of anhydrous DMF. The reactionmixture is poured onto 300 ml of a semisaturated aqueous NaHCO₃ solutionand extracted 3 times with 150 ml of EA each time. The extract is driedover Na₂SO₄ and the solvent is removed in vacuo. Chromatography onsilica gel using EA/HEP 1:2 yields 1.2 g of a colorless oil.

R_(f)(EA/HEP 1:2)=0.16 MS (FAB): 454 (M+H)⁺

g)4′-(4-Chloro-5-formyl-2-phenylimidazol-1-ylmethyl)-3′-methanesulfonylbiphenyl-2-sulfonicacid tert-butylamide

970 mg of3-(4-bromo-3-methanesulfonylbenzyl)-5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde,660 mg of N-tert-butyl-2-dihydroxyboran-2-ylbenzenesulfonamide (J. Med.Chem. 1997, 40, 547), 24 mg of Pd(II) acetate and 56 mg oftriphenylphosphine are taken up in 13 ml of toluene and 3.5 ml ofethanol and 2.1 ml of an aqueous 2 M Na₂CO₃ solution are added. Thereaction mixture is refluxed for 105 minutes, then allowed to cool to RTand taken up in 200 ml of a semisaturated aqueous NaHCO₃ solution. Themixture is extracted 3 times using 150 ml of EA each time, dried overNa₂SO₄ and the solvent is removed in vacuo. Chromatography on silica gelusing EA/HEP 1:2 yields 660 mg of a colorless oil.

R_(f)(EA/HEP 1:2)=0.12 MS (ES): 587 (M+H)⁺

h)4′-(4-Chloro-5-formyl-2-phenylimidazol-1-ylmethyl)-3′-methanesulfonylbiphenyl-2-sulfonamide

650 mg of4′-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)-3′-methanesulfonylbiphenyl-2-sulfonicacid tert-butylamide are dissolved in 5.6 ml of trifluoroacetic acid and133 μl of anisole are injected. The mixture is stirred at RT for 8hours, then the volatile constituents are removed in vacuo. The residueis again taken up in 20 ml of water 3 times and the water is thenremoved in vacuo. Finally, the residue is suspended 2 more times in 30ml of toluene each time and the volatile constituents are again removedin vacuo. 570 mg of a pale yellow solid are obtained, which is reactedfurther without purification because of inadequate solubility.

R_(f)(EA/HEP 2:1)=0.24

i)4′-[5-Formyl-4-(2-methoxyethoxy)-2-phenylimidazol-1-ylmethyl]-3′-methanesulfonylbiphenyl-2-sulfonamide

330 mg of4′-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)-3′-methanesulfonylbiphenyl-2-sulfonamideand 250 mg of NaOH are stirred at 90° C. for 2 hours in 12.5 ml ofmethoxyethanol. The reaction mixture is subsequently cooled to RT andsubsequently poured onto 100 ml of a semisaturated aqueous NaHCO₃solution. It is extracted 3 times with 100 ml of EA each time, driedover Na₂SO₄ and the solvent is removed in vacuo. 350 mg of a colorlessoil are obtained, which immediately has to be employed further withoutpurification because of surprising instability.

R_(f)(EA/HEP 2:1)=0.18

j)4′-[5-Formyl-4-(2-methoxyethoxy)-2-phenylimidazol-1-ylmethyl]-3′-methanesulfonylbiphenyl-2-sulfonylcyanamide

340 mg of4′-[5-formyl-4-(2-methoxyethoxy)-2-phenylimidazol-1-ylmethyl]-3′-methanesulfonylbiphenyl-2-sulfonamideare reacted according to the general procedure for the preparation ofsulfonylcyanamides from sulfonamides (reaction time 15 minutes) and,after chromatography on silica gel using EA/MeOH 1:5, 90 mg of whitecrystals are obtained, mp>270° C.

R_(f)(EA/MeOH 1:5)=0.27 IR (C≡N): 2178.1 cm⁻¹ MS (FAB): 595 (M+H)⁺

Example 23′-Chloro-4′-[5-formyl-4-(2-methoxyethoxy)-2-phenylimidazol-1-ylmethyl]-biphenyl-2-sulfonylcyanamide

a) 4-Bromo-1-bromomethyl-2-chlorobenzene

7.1 ml of 4-bromo-2-chlorotoluene are dissolved in 20 ml ofchlorobenzene and treated in portions at 130° C. with a mixture of 9.4 gof N-bromosuccinimide and 200 mg of dibenzoyl peroxide. The mixture isrefluxed for 30 minutes, diluted with 100 ml of CH₂Cl₂ after cooling andwashed once each with 50 ml of a saturated aqueous Na₂SO₃ solution and100 ml of a saturated aqueous NaHCO₃ solution. It is dried over Na₂SO₄and the solvent is removed in vacuo. 11.0 g of a pale yellow oil areobtained.

R_(f)(EA/HEP 1:8)=0.49 MS (DCI): 283 (M+H)⁺

b)3-(4-Bromo-2-chlorobenzyl)-5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde

1.5 g of 4-chloro-5-formyl-2-phenylimidazole (Chem. Pharm. Bull. 1976,24(5), 960), 5.8 g of K₂CO₃ and 8.0 g of4-bromo-1-bromomethyl-2-chlorobenzene are stirred at RT for 24 h in 50ml of DMF. The mixture is then diluted with 250 ml of EA and washedtwice each with 100 ml of water and once with 100 ml of a saturatedaqueous NaCl solution. It is dried over Na₂SO₄ and the solvents areremoved in vacuo. Chromatography on silica gel using EA/HEP 1:4 yields2.2 g of a colorless oil.

R_(f)(EA/HEP 1:4)=0.47 MS (ES): 411 (M+H)⁺

c)3′-Chloro-4′-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfonicacid tert-butylamide

2.2 g of3-(4-bromo-2-chlorobenzyl)-5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde,2.0 g of N-tert-butyl-2-dihydroxyboran-2-ylbenzenesulfonamide (J. Med.Chem. 1997, 40, 547), 140 mg of triphenylphosphine, 64 mg of Pd(II)acetate and 1.2 g of Na₂CO₃ are dissolved in 30 ml of toluene, 10 ml ofethanol and 10 ml of water and refluxed for 3 h. After cooling, 200 mlof a saturated aqueous NaHCO₃ solution are added and the mixture isextracted 3 times with 200 ml of EA each time. It is dried over MgSO₄and the solvent is removed in vacuo. Chromatography on silica gel yields1.5 g of a colorless foam.

R_(f)(DIP)=0.25 MS (ES): 542 (M+H)⁺

d)3′-Chloro-4′-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfonamide

1.5 g of3′-chloro-4′-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfonicacid tert-butylamide and 340 μl of anisole are dissolved in 10 ml oftrifluoroacetic acid and stirred at RT for 24 h. The volatileconstituents are removed in vacuo, the residue is taken up twice with 50ml of toluene each time and the volatile constituents are again removedin vacuo. 1.5 g of a colorless foam are obtained.

R_(f)(DIP)=0.15 MS (ES): 486 (M+H)⁺

e)3′-Chloro-4′-[5-formyl-4-(2-methoxyethoxy)-2-phenylimidazol-1-ylmethyl]biphenyl-2-sulfonamide

280 mg of3′-chloro-4′-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfonamideand 230 mg of NaOH are stirred at 90° C. for 3 hours in 11.5 ml ofmethoxyethanol. After cooling, the reaction mixture is taken up in 150ml of a semisaturated aqueous NaHCO₃ solution and extracted 3 timesusing 100 ml of EA each time. The extract is dried over Na₂SO₄ and thesolvent is removed in vacuo. 310 mg of a colorless oil are obtained,which is directly reacted further without purification.

R_(f)(EA/HEP 2:1)=0.37

f)3′-Chloro-4′-[5-formyl-4-(2-methoxyethoxy)-2-phenylimidazol-1-ylmethyl]biphenyl-2-sulfonylcyanamide

69 mg of3′-chloro-4′-[5-formyl-4-(2-methoxyethoxy)-2-phenylimidazol-1-ylmethyl]biphenyl-2-sulfonamideare reacted according to the general procedure for the preparation ofsulfonylcyanamides from sulfonamides (reaction time 1 hour) and, afterchromatography on silica gel using EA/MeOH 1:5, 63 mg of white crystalsare obtained, mp 195° C. (with decomposition).

R_(f)(EA/MeOH 1:5)=0.33 IR (C≡N): 2178.6 cm⁻¹ MS (ES): 552 (M+H)⁺

Example 34′-[5-Formyl-2-(4-isopropylphenyl)-4-(2-methoxyethoxy)imidazol-1-ylmethyl]biphenyl-2-sulfonylcyanamide

a)4′-[4-Chloro-5-formyl-2-(4-isopropylphenyl)imidazol-1-ylmethyl]biphenyl-2-sulfonicacid dimethylaminomethylenamide

1.2 g of 5-chloro-2-(4-isopropylphenyl)-3H-imidazole-4-carbaldehyde(synthesized analogously to Chem. Pharm. Bull. 1976, 24(5), 960), 1.9 gof 4′-bromomethylbiphenyl-2-sulfonic acid dimethylaminomethylenamide and0.69 g of K₂CO₃ are suspended in 25 ml of anhydrous DMF and stirred atRT for 8 hours. A further 0.38 g of 4′-bromomethylbiphenyl-2-sulfonicacid dimethylaminomethylenamide are added and the mixture is stirred atRT for a further 5 hours. The reaction mixture is diluted with 300 ml ofa 10% aqueous NaHCO₃ solution and extracted 3 times using 150 ml of EAeach time. The extract is dried over Na₂SO₄ and the solvent is removedin vacuo. Chromatography on silica gel using EA/HEP 2:1 yields 1.9 g ofa colorless, crystalline solid, mp 177° C.

R_(f)(EA/HEP 2:1)=0.28 MS (ES): 550 (M+H)⁺

b)4′-[4-Chloro-5-formyl-2-(4-isopropylphenyl)imidazol-1-ylmethyl]biphenyl-2-sulfonamide

1.9 g of4′-[4-chloro-5-formyl-2-(4-isopropylphenyl)imidazol-1-ylmethyl]biphenyl-2-sulfonicacid dimethylaminomethylenamide are dissolved in 35 ml of MeOH, 18 ml ofa saturated aqueous HCl solution are added and the mixture is refluxedfor 90 minutes. After cooling, it is adjusted to pH=5-6 using a 6Naqueous NaOH solution and the precipitated product is filtered off. Itis washed 3 times with 20 ml of water each time and the product is driedat 60° C. in a fine vacuum. 1.4 g of an amorphous solid are obtained.

R_(f)(EA/HEP 1:1)=0.25 MS (ES): 495 (M+H)⁺

c)4′-[4-Chloro-5-formyl-2-(4-isopropylphenyl)imidazol-1-ylmethyl]biphenyl-2-sulfonylcyanamide

198 mg of4′-[4-chloro-5-formyl-2-(4-isopropylphenyl)imidazol-1-ylmethyl]biphenyl-2-sulfonamideand 166 mg of K₂CO₃ are suspended in 2 ml of anhydrous acetonitrile and80 μl of a 5N BrCN solution in acetonitrile are injected. The mixture isrefluxed for one hour. After cooling, the entire reaction mixture ischromatographed on silica gel using EA/MeOH 5:1 and 170 mg of acrystalline solid are obtained, mp 217-218° C. (with decomposition).

R_(f)(EA/MeOH 5:1)=0.38 MS (ES): 520 (M+H)⁺

d)4′-[5-Formyl-2-(4-isopropylphenyl)-4-(2-methoxyethoxy)imidazol-1-ylmethyl]biphenyl-2-sulfonylcyanamide

140 mg of4′-[4-chloro-5-formyl-2-(4-isopropylphenyl)imidazol-1-ylmethyl]biphenyl-2-sulfonylcyanamideand 108 mg of NaOH are dissolved in 5 ml of methoxyethanol and stirredat 90° C. for 105 minutes. After cooling, the mixture is taken up with150 ml of a 10% aqueous NaHCO₃ solution and extracted 3 times using 100ml of EA each time. It is dried over Na₂SO₄ and the solvent is removedin vacuo. Chromatography on silica gel using EA/MeOH 10:1 yields 90 mgof an amorphous solid.

R_(f)(EA/MeOH 10:1)=0.29 MS (ES): 559 (M+H)⁺

Example 44′-[5-Formyl-4-(2-methoxyethoxy)-2-phenylimidazol-1-ylmethyl]-3′-(2-methoxyethoxy)biphenyl-2-sulfonylcyanamide

a) 4-Methyl-3-(2-methoxy)ethoxyaniline

22.0 g of 3-hydroxy-4-methylaniline, 24.9 g of 2-bromoethyl methyl etherand 233 g of Cs₂CO₃ are dissolved in 570 ml of DMF and stirred at 40° C.for 8 h. 3 of a 10% aqueous sodium hydrogencarbonate solution are added,the mixture is extracted 6 times using 750 ml of EA each time and washedtwice using 1 of a 10% aqueous sodium hydrogencarbonate solution eachtime. It is dried over sodium sulfate and the solvent is removed invacuo. 32.9 g of a yellow oil are obtained, which is employed further assuch.

R_(f)(EA/HEP 1:1)=0.33

b) 4-Methyl-3-(2-methoxy)ethoxybromobenzene

32.8 g of 4-methyl-3-(2-methoxy)ethoxyaniline are suspended in 660 ml ofa semisaturated aqueous HBr solution and a solution of 12.5 g of NaNO₃in 25 ml of water is slowly added dropwise at 0° C. The mixture issubsequently stirred at 0° C. for 30 minutes and this solution issubsequently slowly added to a solution, heated to 50° C. of 51.9 g ofCuBr in 490 ml of a saturated aqueous HBr solution. The reaction mixtureis then slowly heated from 50° C. to 70° C. over a period of 6 h. Aftersubsequent cooling, it is extracted 4 times using 500 ml of diethylether each time, washed with 500 ml of a saturated aqueous NaCl solutionand dried over sodium sulfate. Chromatography on silica gel using EA/HEP1:8 yields 15.4 g of a colorless oil.

R_(f)(EA/HEP 1:1)=0.41 MS (DCI): 245 (M+H)⁺

c) 4-Bromomethyl-3-(2-methoxy)ethoxybromobenzene

15.3 g of 4-methyl-3-(2-methoxy)ethoxybromobenzene are dissolved in 300ml of chlorobenzene and a mixture of 11.1 g of N-bromosuccinimide and125 mg of benzoyl peroxide is added in portions under reflux. Themixture is refluxed for 24 h, the solvent is removed in vacuo and theresidue is subsequently taken up with 500 ml of CH₂Cl₂. The mixture iswashed first with 200 ml of a saturated aqueous Na₂SO₄ solution, thenwith 100 ml of a saturated aqueous sodium carbonate solution. It isdried over sodium sulfate and the solvent is removed in vacuo.Chromatography on silica gel using EA/HEP 1:15 yields 12.8 g of a paleyellow oil.

R_(f)(EA/HEP 1:4)=0.42 MS (DCI): 323 (M+H)⁺

d)3-[4-Bromo-2-(2-methoxyethoxy)benzyl]-5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde

620 mg of 5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde, 970 mg of4-bromo-1-bromomethyl-2-(2-methoxyethoxy)benzene and 415 mg of K₂CO₃ aresuspended in 15 ml of anhydrous DMF and stirred at RT for 15 hours. Themixture is taken up with 75 ml of a saturated aqueous Na₂CO₃ solutionand 75 ml of water and extracted 3 times using 100 ml of EA each time.It is dried over Na₂SO₄ and the solvent is removed in vacuo.Chromatography on silica gel using EA/HEP 1:4 yields 640 mg of acolorless oil.

R_(f)(EA/HEP 1:2)=0.26 MS (ES): 450 (M+H)⁺

e)4′-(4-Chloro-5-formyl-2-phenylimidazol-1-ylmethyl)-3′-(2-methoxyethoxy)biphenyl-2-sulfonicacid tert-butylamide

620 mg of3-[4-bromo-2-(2-methoxyethoxy)benzyl]-5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde,420 mg of 2-dihydroxyborylbenzenesulfonic acid tert-butylamide, 16 mg ofPd(II) acetate and 36 mg of triphenylphosphine are dissolved in 8 ml oftoluene and 2 ml of ethanol and 1.4 ml of a 2N aqueous Na₂CO₃ solutionare added. The reaction mixture is refluxed for 4 hours and, aftercooling, it is diluted with 75 ml of a saturated aqueous Na₂CO₃ solutionand 75 ml of water. It is extracted 3 times using 100 ml of EA eachtime. The extract is dried over Na₂SO₄ and the solvent is removed invacuo. Chromatography on silica gel using EA/HEP 1:2 yields 600 mg of acolorless oil.

R_(f)(EA/HEP 1:2)=0.20 MS (ES): 583 (M+H)⁺

f)4′-(4-Chloro-5-formyl-2-phenylimidazol-1-ylmethyl)-3′-(2-methoxyethoxy)biphenyl-2-sulfonamide

570 mg of4′-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)-3′-(2-methoxyethoxy)biphenyl-2-sulfonicacid tert-butylamide are dissolved in 5 ml of trifluoroacetic acid and117 μl of anisole are added. The mixture is stirred at RT for 8 h, thenthe solvent is removed in vacuo. Chromatography on silica gel usingEA/HEP 1:1 yields 350 mg of an amorphous solid.

R_(f)(EA/HEP 1:1)=0.27 MS (ES): 527 (M+H)⁺

g)4′-[5-Formyl-4-(2-methoxyethoxy)-2-phenylimidazol-1-ylmethyl]-3′-(2-methoxyethoxy)biphenyl-2-sulfonamide

340 mg of4′-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)-3′-(2-methoxyethoxy)biphenyl-2-sulfonamideand 260 mg of NaOH are dissolved in 13 ml of 2-methoxyethanol andstirred at 90° C. for 7 hours. After cooling, the reaction mixture isdiluted with 100 ml of a 10% aqueous NaHCO₃ solution and extracted 3times using 100 ml of EA each time. The extract is dried over Na₂SO₄ andthe solvent is removed in vacuo. Chromatography on silica gel usingEA/HEP 2:1 yields 230 mg of an amorphous solid.

R_(f)(EA/HEP 2:1)=0.33 MS (ES): 566 (M+H)⁺

h)4′-[5-Formyl-4-(2-methoxyethoxy)-2-phenylimidazol-1-ylmethyl]-3′-(2-methoxyethoxy)biphenyl-2-sulfonylcyanamide

210 mg of4′-[5-formyl-4-(2-methoxyethoxy)-2-phenylimidazol-1-ylmethyl]-3′-(2-methoxyethoxy)biphenyl-2-sulfonamideand 154 mg of K₂CO₃ are suspended in 4 ml of anhydrous acetonitrile and74 μl of a 5N solution of BrCN in actonitrile are injected. The mixtureis refluxed for 3 hours and, after cooling, the entire reaction mixtureis chromatographed on silica gel using EA/MeOH 10:1. 170 mg of whitecrystals are obtained, mp 162° C.

R_(f)(EA/MeOH 10:1)=0.11 MS (ES): 591 (M+H)⁺

Pharmacological Data

Inhibition of the Na⁺-dependent Cl⁻/HCO₃ ⁻ Exchanger (NCBE) in HumanEndothelial Cells

Human endothelial cells (ECV-304) were detached from culture bottleswith the aid of trypsin/EDTA buffer (0.05/0.02% in phosphate buffer)and, after centrifugation (100 g, 5 min), taken up in a buffered saltsolution (mmol/l: 115 NaCl, 20 NH₄Cl, 5 KCl, 1 CaCl₂, 1 MgSO₄, 20N-(2-hydroxyethyl)piperazine-N-2-ethanesulfonic acid (HEPES), 5 glucoseand 1 g/l of bovine serum albumin; pH 7.4). This cell suspension wasincubated at 37° C. for 20 min with 5 μM BCECF-acetoxymethyl ester. Thecells were then washed and resuspended in a sodium- and bicarbonate-freebuffer solution (mmol/l: 5 HEPES, 133.8 choline chloride, 4.7 KCl, 1.25MgCl₂, 0.97 K₂HPO₄, 0.23 KH₂PO₄, 5 glucose; pH 7.4).

For subsequent fluorescence measurement in an FLIPR (Fluorescent ImagingPlate Reader) 100 μl of this cell suspension having 20,000 cells in eachcase were pipetted per well into a 96-well microtiter plate and thismicrotiter plate was centrifuged (100 g, 5 min).

In the FLIPR, 100 μl of buffer solution in each case were then removedfrom a further pretreated microtiter plate and pipetted into each of the96 wells of the measurement plate. A bicarbonate- and sodium-containingbuffer solution (mmol/l: 5 HEPES, 93.8 NaCl, 40 NaHCO₃, 4.7 KCl, 1.25CaCl₂, 1.25 MgCl₂, 0.97 Na₂HPO₄, 0.23 NaH₂PO₄, 5 glucose; pH 7.4) whichcontained 50 μM HOE 642 was used for a 100% control, i.e. a recovery ofthe intracellular pH (pH_(i)) via the NCBE. For a 0% control, i.e. nopH_(i) recovery at all, a bicarbonate-free, sodium-containing buffersolution (mmol/l: 5 HEPES, 133.8 NaCl, 4.7 KCl, 1.25 CaCl₂, 1.25 MgCl₂,0.97 Na₂HPO₄, 0.23 NaH₂PO₄, 5 glucose; pH 7.4) was employed, to which 50μM HOE 642 were likewise added. The compounds according to the inventionwere added to the sodium- and bicarbonate-containing solution in variousconcentrations.

After addition of the buffer solutions to the dye-loaded, acidifiedcells in the measurement plate, the rise in the fluorescence intensity,which corresponded to a rise in the pH_(i), in each well of themicrotiter plate was determined. The kinetics were in this case recordedat 35° C. for a period of 2 minutes.

The increase in the fluorescence intensities for differentconcentrations of the compounds according to the invention was relatedto the two controls and from this the inhibitory action of thesubstances was determined.

Results

Residual activity of the NCBE at an inhibitor concentration of 10 μM (in%)

Compound of Example No. 1  9.8 2 18.9 3 29.6 4 13.5

What is claimed is:
 1. A compound of the formula I

in which the symbols have the following meaning: R(1) is hydrogen, alkylhaving 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or —C_(a)H_(2a)-phenyl,where the phenyl moiety is unsubstituted or substituted by 1, 2 or 3identical or different radicals representing F, Cl, Br, I, CF₃, methyl,methoxy, hydroxyl or NR(8)R(9); R(8) and R(9) independently of oneanother are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; a iszero, 1 or 2; or R(1) is —C_(b)H_(2b)-heteroaryl having 1, 2, 3, 4, 5,6, 7, 8 or 9 carbon atoms, where the heteroaryl moiety is unsubstitutedor substituted by 1, 2 or 3 identical or different radicals representingF, Cl, Br, I, CF₃, methyl, methoxy, hydroxyl or NR(10)R(11); R(10) andR(11) independently of one another are hydrogen or alkyl having 1, 2, 3or 4 carbon atoms; b is zero, 1 or 2; or R(1) is —C_(d)H_(2d)-cycloalkylhaving 3, 4, 5, 6 or 7 carbon atoms; d is zero, 1 or 2; R(2) and R(3)independently of one another are hydrogen, F, Cl, Br, I, CF₃, —CN, —NO₂,CH₂OR(17), CO—R(6), O—R(7), O-(alkylene having 2, 3 or 4 carbonatoms)-O—R(17) or NR(50)R(51); R(17) is hydrogen or alkyl having 1, 2,3, 4, 5, 6, 7 or 8 carbon atoms; R(6) is hydrogen, alkyl having 1, 2, 3,4, 5, 6, 7 or 8 carbon atoms, OR(30) or phenyl which is unsubstituted orsubstituted by 1, 2 or 3 identical or different radicals representing F,Cl, Br, I, CF₃, methyl, methoxy, hydroxyl or NR(31)R(32); R(31) andR(32) independently of one another are hydrogen or alkyl having 1, 2, 3or 4 carbon atoms; R(30) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7or 8 carbon atoms; R(50) and R(51) independently of one another are-(alkylene having 2, 3 or 4 carbon atoms)-O—R(52); R(52) is hydrogen oralkyl having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; R(7) is hydrogen,alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or phenyl, which isunsubstituted or substituted by 1, 2 or 3 identical or differentradicals representing F, Cl, Br, I, CF₃, methyl, methoxy, hydroxyl orNR(12)R(13); R(12) and R(13) independently of one another are hydrogenor alkyl having 1, 2, 3 or 4 carbon atoms; or R(7) is heteroaryl having1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, which is unsubstituted orsubstituted by 1, 2 or 3 identical or different radicals representing F,Cl, Br, I, CF₃, methyl, methoxy, hydroxyl or NR(14)R(15); R(14) andR(15) independently of one another are hydrogen or alkyl having 1, 2, 3or 4 carbon atoms; or R(2) and R(3) independently of one another arealkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3,4, 5, 6 or 7 carbon atoms or —C_(g)H_(2g)-phenyl, where the phenylmoiety is unsubstituted or substituted by 1, 2 or 3 identical ordifferent radicals representing F, Cl, Br, I, CF₃, methyl, methoxy,hydroxyl or NR(18)R(19); R(18) and R(19) independently of one anotherare hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; g is zero, 1 or2; or R(2) and R(3) independently of one another are—C_(l)H_(2l)-heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,where the heteroaryl moiety is unsubstituted or substituted by 1, 2 or 3identical or different radicals representing F, Cl, Br, I, CF₃, methyl,methoxy, hydroxyl or NR(20)R(21); R(20) and R(21) independently of oneanother are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; I iszero, 1 or 2; or R(2) and R(3) independently of one another areSO_(n)—R(22); n is zero, 1 or 2; R(22) is alkyl having 1, 2, 3, 4, 5, 6,7 or 8 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or—C_(s)C_(2s)-phenyl which is unsubstituted or substituted by 1, 2 or 3identical or different radicals representing F, Cl, Br, I, CF₃, methyl,methoxy, hydroxyl or NR(34)R(35); R(34) and R(35) independently of oneanother are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; s iszero, 1 or 2; R(4) and R(5) independently of one another are hydrogen,alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, F, Cl, Br, I, CF₃,—CN, —NO₂, SO_(p)—R(16), CO—R(23), O—R(24) or O-(alkylene having 2, 3 or4 carbon atoms)-O—R(33); p is zero, 1 or 2; R(16) is alkyl having 1, 2,3, 4, 5, 6, 7 or 8 carbon atoms or phenyl, which is unsubstituted orsubstituted by 1, 2 or 3 identical or different radicals representing F,Cl, Br, I, CF₃, methyl, methoxy, hydroxyl or NR(26)R(27); R(26) andR(27) independently of one another are hydrogen or alkyl having 1, 2, 3or 4 carbon atoms; R(23) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7or 8 carbon atoms, or OR(25); R(25) is hydrogen, alkyl having 1, 2, 3,4, 5, 6, 7 or 8 carbon atoms; R(24) is hydrogen, alkyl having 1, 2, 3,4, 5, 6, 7 or 8 carbon atoms, or phenyl, which is unsubstituted orsubstituted by 1, 2 or 3 identical or different radicals representing F,Cl, Br, I, CF₃, methyl, methoxy, hydroxyl or NR(28)R(29); R(28) andR(29) independently of one another are hydrogen or alkyl having 1, 2, 3or 4 carbon atoms; R(33) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7or 8 carbon atoms; or a physiologically tolerable salt thereof; with theproviso that at least one of the radicals R(2) or R(3) is O-(alkylenehaving 2, 3 or 4 carbon atoms)-O—R(17) or NR(50)R(51).
 2. A compound asclaimed in claim 1, in which R(1) is hydrogen, alkyl having 1, 2, 3 or 4carbon atoms or —C_(a)H_(2a)-phenyl, where the phenyl moiety isunsubstituted or substituted by 1 or 2 identical or different radicalsrepresenting F, Cl, Br, CF₃, methyl, methoxy, hydroxyl or NR(8)R(9);R(8) and R(9) independently of one another are hydrogen or methyl; a iszero or 1; or R(1) is heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9carbon atoms which is unsubstituted or substituted by a radicalrepresenting F, Cl, Br, CF₃, CH₃, methoxy, hydroxyl or NR(10)R(11);R(10) and R(11) independently of one another are hydrogen or methyl; orR(1) is —C_(d)H_(2d)-cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; dis zero or 1; R(2) and R(3) independently of one another are hydrogen,F, Cl, Br, CF₃, —CN, —NO₂, CH₂OR(17), CO—R(6), O—R(7), O-(alkylenehaving 2 or 3 carbon atoms)-O—R(17) or NR(50)R(51); R(17) is hydrogen oralkyl having 1, 2, 3 or 4 carbon atoms; R(6) is hydrogen, alkyl having1, 2, 3 or 4 carbon atoms, OR(30) or phenyl, which is unsubstituted orsubstituted by 1 or 2 identical or different radicals representing F,Cl, Br, CF₃, methyl, methoxy, hydroxyl or NR(31)R(32); R(31) and R(32)independently of one another are hydrogen or methyl; R(30) is hydrogenor alkyl having 1, 2, 3 or 4 carbon atoms; R(7) is hydrogen, alkylhaving 1, 2, 3 or 4 carbon atoms or phenyl, which is unsubstituted orsubstituted by 1 or 2 identical or different radicals representing F,Cl, Br, CF₃, methyl, methoxy, hydroxyl or NR(12)R(13); R(12) and R(13)independently of one another are hydrogen or methyl; or R(7) isheteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, which isunsubstituted or substituted by 1 or 2 identical or different radicalsrepresenting F, Cl, Br, CF₃, methyl, methoxy, hydroxyl or NR(14)R(15);R(14) and R(15) independently of one another are hydrogen or methyl;R(50) and R(51) independently of one another are -(alkylene having 2 or3 carbon atoms)-O—R(52); R(52) is hydrogen or alkyl having 1, 2, 3 or 4carbon atoms; or R(2) and R(3) independently of one another are alkylhaving 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7carbon atoms or —C_(g)H_(2g)-phenyl, where the phenyl moiety isunsubstituted or substituted by 1 or 2 identical or different radicalsrepresenting F, Cl, Br, CF₃, methyl, methoxy, hydroxyl or NR(18)R(19);R(18) and R(19) independently of one another are hydrogen or methyl; gis zero or 1; or R(2) and R(3) independently of one another areheteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, which isunsubstituted or substituted by a radical representing F, Cl, Br, CF₃,methyl, methoxy, hydroxyl or NR(20)R(21); R(20) and R(21) independentlyof one another are hydrogen or methyl; or R(2) and R(3) independently ofone another are SO_(n)—R(22), n is zero, 1 or 2; R(22) is alkyl having1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbonatoms or —C_(s)H_(2s)-phenyl, where the phenyl moiety is unsubstitutedor substituted by 1 or 2 identical or different radicals representing F,Cl, Br, CF₃, methyl, methoxy, hydroxyl or NR(34)R(35); R(34) and R(35)independently of one another are hydrogen or methyl; s is zero or 1;R(4) and R(5) independently of one another are hydrogen, alkyl having 1,2, 3 or 4 carbon atoms, F, Cl, Br, CF₃, —CN, —NO₂, SO_(p)—R(16),CO—R(23), O—R(24) or O-(alkylene having 2 or 3 carbon atoms)-O—R(33); pis zero, 1 or 2; R(16) is alkyl having 1, 2, 3 or 4 carbon atoms orphenyl, which is unsubstituted or substituted by 1 or 2 identical ordifferent radicals representing F, Cl, Br, CF₃, methyl, methoxy,hydroxyl or NR(26)R(27); R(26) and R(27) independently of one anotherare hydrogen or methyl; R(23) is hydrogen, alkyl having 1, 2, 3 or 4carbon atoms, or OR(25); R(25) is hydrogen, alkyl having 1, 2, 3 or 4carbon atoms; R(24) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms,or phenyl, which is unsubstituted or substituted by 1 or 2 identical ordifferent radicals representing F, Cl, Br, CF₃, methyl, methoxy,hydroxyl or NR(28)R(29); R(28) and R(29) independently of one anotherare hydrogen or methyl; R(33) is hydrogen or alkyl having 1, 2, 3 or 4carbon atoms; with the proviso that at least one of the radicals R(2) orR(3) is O-(alkylene having 2 or 3 carbon atoms)-O—R(17) or NR(50)R(51).3. A compound as claimed in claim 1, in which: R(1) is hydrogen, alkylhaving 1, 2, 3 or 4 carbon atoms or phenyl, which is unsubstituted orsubstituted by a radical representing F, Cl, Br, CF₃, methyl, methoxy,hydroxyl or NR(8)R(9); R(8) and R(9) independently of one another arehydrogen or methyl; or R(1) is heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8or 9 carbon atoms, which is unsubstituted or substituted by a radicalrepresenting F, Cl, Br, CF₃, methyl, methoxy, hydroxyl or NR(10)R(11);R(10) and R(11) independently of one another are hydrogen or methyl; orR(1) is cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; R(2) and R(3)independently of one another are hydrogen, F, Cl, Br, CF₃, —CN, —NO₂,CO—R(6) or O—R(7), O—CH₂—CH₂—O—R(17) or NR(50)R(51); R(6) is hydrogen,alkyl having 1, 2, 3 or 4 carbon atoms, OR(30) or phenyl, which isunsubstituted or substituted by a radical representing F, Cl, Br, CF₃,methyl, methoxy, hydroxyl or NR(31)R(32); R(31) and R(32) independentlyof one another are hydrogen or methyl; R(30) is hydrogen or alkyl having1, 2 or 3 carbon atoms; R(7) is hydrogen, alkyl having 1, 2, 3 or 4carbon atoms or phenyl, which is unsubstituted or substituted by aradical representing F, Cl, Br, methyl, methoxy, hydroxyl orNR(12)R(13); R(12) and R(13) independently of one another are hydrogenor methyl; or R(7) is heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9carbon atoms, which is unsubstituted or substituted by a radicalrepresenting F, Cl, Br, CF₃, methyl, methoxy, hydroxyl or NR(14)R(15);R(14) and R(15) independently of one another are hydrogen or methyl;R(17) is methyl or ethyl; R(50) and R(51) independently of one anotherare —CH₂—CH₂—O—R(52); R(52) is methyl or ethyl; or R(2) and R(3)independently of one another are alkyl having 1, 2, 3 or 4 carbon atoms,cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or phenyl, which isunsubstituted or substituted by a radical representing F, Cl, Br, CF₃,methyl, methoxy, hydroxyl or NR(18)R(19); R(18) and R(19) independentlyof one another are hydrogen or methyl; or R(2) and R(3) independently ofone another are heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbonatoms, which is unsubstituted or substituted by a radical representingF, Cl, Br, CF₃, CH₃, methoxy, hydroxyl or NR(20)R(21); R(20) and R(21)independently of one another are hydrogen or methyl; or R(2) and R(3)independently of one another are SO_(n)—R(22); n is zero or 2; R(22) isalkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6 or7 carbon atoms or phenyl which is unsubstituted or substituted by 1 or 2identical or different radicals representing F, Cl, Br, CF₃, methyl,methoxy, hydroxyl or NR(34)R(35); R(34) and R(35) independently of oneanother are hydrogen or methyl; R(4) and R(5) independently of oneanother are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl,CF₃, —CN, —NO₂, SO_(p)—R(16), CO—R(23), O—R(24) or O—CH₂—CH₂—O—R(33); pis zero or 2; R(23) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atomsor OR(25); R(25) is hydrogen, alkyl having 1, 2 or 3 carbon atoms; R(24)is hydrogen, alkyl having 1, 2 or 3 carbon atoms or phenyl, which isunsubstituted or substituted by a radical representing F, Cl, Br, CF₃,methyl, methoxy, hydroxyl or NR(28)R(29); R(28) and R(29) independentlyof one another are hydrogen or methyl; R(16) is alkyl having 1, 2, 3 or4 carbon atoms or phenyl which is unsubstituted or substituted by aradical representing F, Cl, Br, CF₃, methyl, methoxy, hydroxyl orNR(26)R(27); R(26) and R(27) independently of one another are hydrogenor methyl; R(33) is methyl or ethyl; with the proviso that at least oneof the radicals R(2) or R(3) is O—CH₂—CH₂—O—R(17) or NR(50)R(51).
 4. Acompound as claimed in claim 1, in which: R(1) is alkyl having 1, 2, 3or 4 carbon atoms or phenyl which is unsubstituted or substituted by aradical representing F, Cl, CF₃, methyl or methoxy; or R(1) isheteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, which isunsubstituted or substituted by a radical representing F, Cl, CF₃,methyl or methoxy; or R(1) is cycloalkyl having 3, 4, 5, 6 or 7 carbonatoms; R(2) and R(3) independently of one another are hydrogen, F, Cl,CF₃, —CN, CO—R(6), O—R(7), O—CH₂—CH₂—O—CH₃ or NR(50)R(51); R(6) ishydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, OR(30) or phenyl,which is unsubstituted or substituted by a radical representing F, Cl,CF₃, methyl or methoxy; R(30) is hydrogen, methyl or ethyl; R(7) ishydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl, which isunsubstituted or substituted by a radical representing F, Cl, CF₃,methyl or methoxy; or R(7) is heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8or 9 carbon atoms, which is unsubstituted or substituted by a radicalrepresenting F, Cl, Br, CF₃, methyl or methoxy; R(50) and R(51) are—CH₂—CH₂—O—CH₃; or R(2) and R(3) independently of one another are alkylhaving 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7carbon atoms or phenyl, which is unsubstituted or substituted by aradical representing F, Cl, CF₃, methyl or methoxy; or R(2) and R(3)independently of one another are heteroaryl having 1, 2, 3, 4, 5, 6, 7,8 or 9 carbon atoms, which is unsubstituted or substituted by a radicalrepresenting F, Cl, CF₃, methyl or methoxy; or R(2) and R(3)independently of one another are SO_(n)—R(22); n is zero or 2; R(22) isalkyl having 1, 2, 3 or 4 carbon atoms or phenyl which is unsubstitutedor substituted by 1 or 2 identical or different radicals representing F,Cl, CF₃, methyl or methoxy; R(4) and R(5) independently of one anotherare hydrogen, methyl, F, Cl, CF₃, —CN, SO₂—R(16), CO—R(23), O—R(24) orO—CH₂—CH₂—O—CH₃; R(16) is alkyl having 1, 2, 3 or 4 carbon atoms orphenyl which is unsubstituted or substituted by a radical representingF, Cl, CF₃, methyl or methoxy; R(23) is hydrogen, methyl or OR(25);R(25) is hydrogen, methyl or ethyl; R(24) is hydrogen, alkyl having 1,2, 3 or 4 carbon atoms or phenyl, which is unsubstituted or substitutedby a radical representing F, Cl, CF₃, methyl or methoxy; with theproviso that at least one of the radicals R(2) or R(3) isO—CH₂—CH₂—O—CH₃ or NR(50)R(51).
 5. A compound as claimed in claim 1, inwhich R(1) is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,—C_(d)H_(2d)-cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms where d isequal to zero, 1 or 2 or —C_(a)H_(2a)-phenyl, where the phenyl moiety isunsubstituted or substituted by 1, 2 or 3 identical or differentradicals representing F, Cl, Br, I, CF₃, methyl, methoxy, hydroxyl orNR(8)R(9); R(8) and R(9) independently of one another are hydrogen oralkyl having 1, 2, 3 or 4 carbon atoms; a is zero, 1 or 2; R(2) isO-(alkylene having 2, 3 or 4 carbon atoms)-O—R(17) or NR(50)R(51); R(17)is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, R(50)and R(51) independently of one another are -(alkylene 2, 3 or 4 carbonatoms)-O—R(52); R(52) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or8 carbon atoms; R(3) is hydrogen, —CN or CO—R(6); R(6) is hydrogen,alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or OR(30) R(30) ishydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; R(4) ishydrogen, Cl, F, Br, I, SO_(p)—R(16) or O—CH₂—CH₂—O—R(33); p is zero, 1or 2; R(16) is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms orphenyl which is unsubstituted or substituted by 1, 2 or 3 identical ordifferent radicals representing F, Cl, Br, I, CF₃, methyl, methoxy,hydroxyl or NR(26)R(27); R(26) and R(27) independently of one anotherare hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R(33) is methylor ethyl; R(5) is hydrogen.
 6. A compound as claimed in claim 1, inwhich: R(1) is —C_(a)H_(2a)-phenyl, where the phenyl moiety isunsubstituted or substituted by 1 or 2identical or different radicalsrepresenting F, Cl, Br, CF₃, methyl, methoxy, hydroxyl or NR(8)R(9);R(8) and R(9) independently of one another are hydrogen or methyl; a iszero or 1; R(2) is O-(alkylene having 2, 3 or 4 carbon atoms)-O—R(17) orNR(50)R(51); R(17) is alkyl having 1, 2, 3 or 4 carbon atoms; R(50) andR(51) independently of one another are -(alkylene having 2, 3 or 4carbon atoms)-O—R(52); R(52) is alkyl having 1, 2, 3 or 4 carbon atoms;R(3) is CO—R(6); R(6) is hydrogen; R(4) is SO₂R(16) where R(16) is alkylhaving 1, 2, 3 or 4 carbon atoms; or O—CH₂—CH₂—O—CH₃; R(5) is hydrogen.7. A compound as claimed in claim 1, in which R(2) is O—CH₂—CH₂—O—R(17)or NR(50)R(51) where R(17) is equal to alkyl having 1, 2, 3 or 4 carbonatoms and R(50) and R(51) are equal to —CH₂—CH₂—O—R(52) where R(52) isequal to alkyl having 1, 2, 3 or 4 carbon atoms.
 8. A pharmaceuticalpreparation, which comprises an effective amount of at least onecompound as claimed in claim 1 and at least one pharmaceutical vehicleor excipient.
 9. A pharmaceutical preparation as claimed in claim 8,which further comprises an effective amount of at least one NHEinhibitor and/or other active substance from another class ofcardiovascular active compound, or a physiologically tolerable saltthereof.
 10. A method for inhibiting the sodium-dependentbicarbonate/chloride exchanger in a host, which comprises administeringto the host an effective amount of at least one compound as claimed inclaim
 1. 11. A method for the treatment or prophylaxis of cardiacinfarct; angina pectoris; an illness caused by an ischemic condition;disturbed respiratory drive; an ischemic condition of the heart or ofthe peripheral or central nervous system; a stroke; an ischemiccondition of a peripheral organ or limb; or an illness in which cellproliferation is a primary or secondary cause, which comprisesadministering to a host in need of the therapy or prophylaxis aneffective amount of at least one compound as claimed in claim
 1. 12. Amethod for the treatment of a state of shock, which comprisesadministering to a host in need of the treatment an effective amount ofat least one compound as claimed in claim
 1. 13. A method for thepreservation or storage of an organ, which comprises contacting theorgan with an effective amount of at least one compound as claimed inclaim
 1. 14. A method for the treatment of atherosclerosis, a latediabetic complication, a carcinomatous disorder, a fibrotic disorder,organ hypertrophy, hyperplasia, or a combination of two or more of theabove, which comprises administering to a host in need of the treatmentan effective amount of at least one compound as claimed in claim
 1. 15.A method for the treatment or prophylaxis of cardiac infarct; anginapectoris; an illness caused by an ischemic condition; disturbedrespiratory drive; an ischemic condition of the heart or of theperipheral or central nervous system; a stroke; an ischemic condition ofa peripheral organ or limb; or an illness in which cell proliferation isa primary or secondary cause, which comprises administering to a host inneed of the therapy or prophylaxis an effective amount of apharmaceutical preparation as claimed in claim
 8. 16. A method for thetreatment of a state of shock, which comprises administering to a hostin need of the treatment an effective amount of a pharmaceuticalpreparation as claimed in claim
 8. 17. A method for the preservation orstorage of an organ, which comprises contacting the organ with aneffective amount of a pharmaceutical preparation as claimed in claim 8.18. A method for the treatment of atherosclerosis, a late diabeticcomplication, a carcinomatous disorder, a fibrotic disorder, organhypertrophy, hyperplasia, or a combination of two or more of the above,which comprises administering to a host in need of the treatment aneffective amount of a pharmaceutical preparation as claimed in claim 8.